Iron(III)-catalyzed denitration reaction: One-pot three-component synthesis of imidazo[1,2-a]pyridine derivatives

Article abstract of DOI:10.1002/ejoc.201301658

An iron(III)-catalyzed one-pot three-component cross-coupling nitration reaction of 2-aminopyridines, aldehydes and nitroalkanes, straightforwardly forms imidazo[1,2-a]pyridine derivatives and is described in this report. The system shows good functional-group tolerance and proceeds smoothly in moderate to good yields. An iron(III)-catalyzed one-pot three-component cross-coupling nitration reaction of 2-aminopyridines, aldehydes, and nitroalkane, leading to the straightforward formation of imidazo[1,2-a]pyridine derivatives has been reported. In this procedure, the starting materials are commercially available. The system shows good functional-group tolerance and proceeds smoothly in moderate to good yields. Copyright

Full text of DOI:10.1002/ejoc.201301658

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201301658
Iron(III)-Catalyzed Denitration Reaction: One-Pot Three-Component Synthesis
of Imidazo[1,2-a]pyridine Derivatives
Hao Yan,[a,b] Yuling Wang,[a,b] Congming Pan,[c] Hao Zhang,[a,b] Sizhuo Yang,[a,b]
Xiaoyu Ren,[a,b] Jian Li,[a,b] and Guosheng Huang*[a,b]
Keywords: Synthetic methods / Multicomponent reactions / Nitrogen heterocycles / Iron
An iron(III)-catalyzed one-pot three-component cross-cou-
pling nitration reaction of 2-aminopyridines, aldehydes and
nitroalkanes, straightforwardly forms imidazo[1,2-a]pyridine
derivatives and is described in this report. The system shows
good functional-group tolerance and proceeds smoothly in
moderate to good yields.
aminopyridines with α-halogeno ketones to synthesize
imidazo[1,2-a]pyridines.[14] Construction of imidazo[1,2-a]-
pyridines through three-component coupling of 2-amino-
pyridines, aldehydes and isonitriles[13b,15] was achieved by
the DiMauro group and Adib group, respectively. Nam-
boothiri et al. have synthesized imidazo[1,2-a]pyridines
from Morita–Baylis–Hillman acetates of nitroalkenes,[11l]
and we obtained imidazo[1,2-a]pyridines by using 2-amino-
pyridine and 2-methyl-nitroolefins.[16] Although the litera-
ture on imidazo[1,2-a]pyridine syntheses has enjoyed a rich
history of versatile methods, most of these methods are not
environmentally benign owing to the use of halogeno com-
pounds, or are limited because of multistep preparations of
the starting materials. Therefore, finding an easy and ef-
ficient method to construct imidazo[1,2-a]pyridines by
using environmentally friendly reagents with simple and
readily accessible substrates is still desirable. Iron is one of
the most abundant, inexpensive and environmentally
friendly metals[17] on earth. In addition, many iron salts and
complexes are readily accessible, thus, iron is highly valued
for easy and efficient methodologies to molecular construc-
tion. To the best of our knowledge, only a few approaches
have been reported based on iron-catalyzed denitration[18]
reactions. For example, Chen and co-workers introduced
the construction of imidazole derivatives by using this strat-
egy. The Hajra group also reported the synthesis of imid-
azo[1,2-a]pyridines from 2-aminopyridine and nitroolefins
through iron-catalyzed denitration reaction.[18a] In spite of
Introduction
Multicomponent reactions[1] have been used frequently
as powerful methods in material, medical, drug, and or-
ganic chemistry to provide structural diversity[2] by syn-
thetic chemists. Various multicomponent reactions have
proven to be efficient and have received considerable inter-
est because they offer prominent advantages such as reduc-
ing time, saving cost and energy, and also create complex
structures from commercially available starting materials.
Considering the features of multicomponent reactions, de-
veloping new and efficient routes for their synthesis has
been recognized as one of the most important topics in re-
cent years.
The imidazo[1,2-a]pyridine scaffold is a 5,6-fused nitro-
gen bridgehead heterocycle, which is one of the most signifi-
cant structural units. It exhibits widespread applications in
medicinal chemistry[3] and materials science,[4] and is also
found in important pharmaceuticals and various bioactive
compounds (Figure 1), such as saripidem (I),[5] olprinone
(II),[6] zolimidine (III),[7] zolpidem(IV),[8] soraprazan (V),[9]
and alpidem (VI).[10] Consequently, the construction of
imidazo[1,2-a]pyridines has attracted a considerable atten-
tion.[11] Recently, with the development of transition-metal-
catalyzed cascade reactions,[12] a variety of approaches
based on N–H and C–H activation have been discovered.[13]
Gryko and co-workers reported the condensation of 2-
[a] State Key Laboratory of Applied Organic Chemistry, Lanzhou these methods, synthesizing imidazo[1,2-a]pyridines
University,
through an iron-catalyzed denitration multicomponent re-
Lanzhou 730000, P. R. China
action has rarely been reported. As a part of our continuing
studies into the synthesis of heterocycles,[19] we paid atten-
tion to designing a new strategy for straightforward access
to imidazo[1,2-a]pyridine rings through a denitration reac-
tion catalyzed by iron(III) in a one-pot three-component
reaction, involving the assembly of the scaffold from
[3+1+1] atom fragments (Scheme 1). The method is facile,
E-mail: hgs@lzu.edu.cn
http://chem.lzu.edu.cn/ArticleShow.asp?ArtID=1219
[b] Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province,
Lanzhou 730000, P. R. China
[c] Jin Chuan Group CO., Ltd.,
Jinchang 737104, P. R. of China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301658.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
G. Huang et al.
FULL PAPER
Figure 1. Examples of imidazo[1,2-a]pyridines with biological activities.
simple to undertake, uses commercially available starting in either O2 or N2, lower product yields were obtained
materials, is environmentally benign, and shows functional (Table 1, Entry 14 and 15). Finally, the optimized condi-
group tolerance. Herein, we wish to present this simple one- tions were identified (Table 1, Entry 13).
pot synthesis of imidazo[1,2-a]pyridine derivatives.
Table 1. Optimization of reaction conditions.[a]
Scheme 1. Synthesis of imidazo[1,2-a]pyridines thorugh a [3+1+1]
reaction.
Entry Catalyst
t [h]
T [°C]
Yield [%][b]
1
2
3
4
5
6
7
8
FeCl2
FeCl3
FeSO4
Fe(acac)3
FeSO4·7H2O
FeCl3 and AgNO3
FeCl3
FeCl3
FeCl3
FeCl3
–
4
4
4
4
4
4
4
4
2
6
4
4
4
4
4
70
70
70
70
70
70
90
110
90
90
90
90
90
90
90
53
58
55
0
Results and Discussion
50
Initially, the three-component reaction of 2-aminopyr-
idine (1a), benzaldehyde (2a) and EtNO2 (3b) was chosen
as the model. The results are summarized in Table 1. When
the reaction was performed by using FeCl2 as the catalyst
at 70 °C for 4 hours in air, desired 3-methyl-2-arylimid-
azo[1,2-a]pyridine (4aab) was obtained in 53% yield
(Table 1, Entry 1). Then different iron salts were evaluated.
The screening of iron catalysts showed FeCl3 to be superior
relative to FeCl2, FeSO4, Fe(acac)3, FeSO4·7H2O, FeCl3
and AgNO3 (Table 1, Entries 1–6). In addition, no product
was observed without the presence of metal iron salts
(Table 1, Entry 11). Carrying out the reaction at 90 °C im-
proved the yield (Table 1, Entry 7), whereas a continued rise
in temperature did not significantly ameliorate the yield
(Table 1, Entry 8). A longer or shorter reaction time did
not promote the transformation (Table 1, Entries 9 and 10).
trace[c]
75
75
73
73
0
9
10
11
12
13
14
15
FeCl3
FeCl3
FeCl3
FeCl3
60[d]
75[e]
56[f]
61[g]
[a] The reaction was carried out with 1a (0.5 mmol), 2a (0.6 mmol),
and 3b (15 equiv.) with catalyst (0.05 mmol) under air. [b] Yield of
isolated product. [c] FeCl3 (0.05 mmol) and AgNO3 (0.05 mmol)
were used. [d] 5 equiv. of 3b were used. [e] 10 equiv. of 3b were used.
[f] The reaction was performed under an O2 atmosphere. [g] The
reaction was performed under a N2 atmosphere.
Having established the optimal reaction conditions, the
Importantly, when the amount of EtNO2 was reduced to 10 scope with substituted aminopyridines was investigated.
equivalents, the product yield did not decrease proportion- The results are illustrated in Table 2 and show that a variety
ately (Table 1, Entry 13); however, only 60% yield (4aab) of substituted aminopyridines with benzaldehyde and
was isolated in the presence of 5 equiv. of EtNO2 (Table 1, EtNO2 mostly proceed smoothly and to give the corre-
Entry 12). Furthermore, when the reaction was conducted sponding products in moderate to good yields. Various elec-
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
One-Pot Synthesis of Imidazo[1,2-a]pyridines
tron-donating (Me, OBn; Table 2, Entries 1–4, and 10) and Table 2. Substrates scope with aminopyridines.[a]
electron-withdrawing substituents (Cl, Br, F, COOEt;
Table 2, Entries 5–9) on the aminopyridines were tolerated
in this transformation. After further investigation, we found
that the nature of the substituents on the aminopyridines
had some influence on the product yields. 2-Aminopyr-
idines substituted with electron-deficient groups (Table 2,
Entries 5–9) resulted in higher yields than those with elec-
tron-rich ones (Table 2, Entries 1–4, and 10). 5-Substituted
2-aminopyridines gave products in highest yield (Table 2,
Entries 6 and 8). Furthermore, several 2-amino heterocy-
cles, such as 2-aminopyrimidine and 2-aminobenzimid-
azole, were unsuitable for the process and the desired prod-
ucts were not isolated, and only a trace amount of product
was detected from TLC measurement.
Next, the substrate scope with aldehydes was further ex-
amined, as shown in Table 3. We were pleased to note that
the transformation is very general for a wide range of alde-
hydes. Aryl and alkyl aldehydes revealed good reactivity in
this reaction. A variety of electron-donating (Me, OMe;
Table 3, Entries 2–6) and electron-withdrawing substituents
(Cl, Br, F, CN; Table 3, Entries 7–13, 16 and 17) at the aro-
matic ring of the aldehyde were tolerated. In addition, a
bulky naphthyl substituent did not hamper the process and
also gave desired product 4anb, albeit in lower yields
(Table 3, Entry 14). Heteroaryl-substituted substrate furan-
2-carbaldehyde could be converted into target product 4aob
in 57% yield (Table 3, Entry 15). Aliphatic aldehyde (3,7-
dimethyloct-6-en-1-al) was less reactive and led to com-
pound 4arb in 40% yield (Table 3, Entry 18).
Encouraged by the results, we explored the applicability
of this three-component coupling reaction. Under slightly
modified reaction conditions with FeCl3 as catalyst and tet-
rabutylammonium iodide (TBAI) as the base, which could
improve the reaction yield, and MeNO2 as substrate, de-
sired 3-unsubstituted imidazopyridine 4aaa was obtained in
good yield (Table 4, Entry 1). Then we evaluated the scope
of the reaction. As depicted in Table 4, the reaction pro-
ceeded smoothly, but the nature of substituents on the aryl
ring affected the reaction. Substitutes with electron-de-
ficient groups (Table 4, Entries 4–6) resulted in higher yields
than those with electron-rich ones (Table 4, Entries 2, 3,
and 7). Moreover, the SMe group was also well tolerated.
Notably, the reaction with 4-(methylthio) benzaldehyde
gave product 4asa in moderate yield. Further oxidation of
4asa by using meta-chloroperoxybenzoic acid could synthe-
size the drug zolimidine according to the literature
(Scheme 2).[20]
To further demonstrate the use of this method, 2-amino-
pyridines, benzaldehyde and 1-nitropropane were employed
as substrates under standard reaction conditions. The reac-
tion proceeded smoothly, and expected 3-ethyl-2-phenyl-
imidazo[1,2-a]pyridine (4aac) was obtained in 75% yield
(Table 5, Entry 1). Next, we explored the variation of the
benzaldehyde in reactions with 2-aminopyridines, and 1-ni-
tropropane. As expected, the substituent effect was consis-
[a] The reaction was carried out by using 1 (0.5 mmol), 2a
tent with MeNO2 and EtNO2. Substituents with electron-
donating group (Table 5, Entries 2–4) resulted in lower
(0.6 mmol), and 3b (10 equiv.) with catalyst (0.05 mmol) in air.
[b] Yield of isolated product.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
G. Huang et al.
FULL PAPER
Table 3. Substrate scope with aldehydes.
[a] The reaction was carried out by using 1a (0.5 mmol), 2 (0.6 mmol), and 3b (10 equiv.) with catalyst (0.05 mmol) in air. [b] Yield of
isolated product.
yields than those with electron-withdrawing groups as a Lewis acid that promotes the reaction by increasing
(Table 5, Entries 6–9).
the electrophilicity of imine 5 through coordination, provid-
On the basis of the above experimental observations, a ing a good electrophilic substrate for nucleophilic nitro-
plausible mechanism for this reaction is outlined in alkane 3. Then 3 reacts with imine 5 through a Michael
Scheme 3. The first step involves coupling of substrates 1 addition reaction to give intermediate 6. Subsequently, an
and 2 to produce imine 5. Presumably, FeIII chloride acts internal proton transfer and intramolecular second Michael
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
One-Pot Synthesis of Imidazo[1,2-a]pyridines
Table 4. Substrate scope with aminopyridines and aldehydes.
Table 5. Substrates scope of aldehydes.
[a] The reaction was carried out by using
(0.6 mmol), TBAI (0.5 mmol) and 3a (10 equiv.) with catalyst
(0.05 mmol) in air. [b] Yield of isolated product.
1 (0.5 mmol), 2
[a] The reaction was carried out by using 1a (0.5 mmol), 2
(0.6 mmol), and 3c (10 equiv.) with catalyst (0.05 mmol) in air.
[b] Yield of isolated product.
Scheme 2. Synthetic approach towards zolimidine.
addition reaction from the pyridine nitrogen in a regioselec-
tive 5-exo-trig fashion lead to intermediate 7. Finally, inter-
mediate 7, upon the removal of water and nitroxyl and the
release of the catalyst, collapses to product 4.[21]
Scheme 3. Plausible reaction mechanism.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
G. Huang et al.
FULL PAPER
1 H), 6.82–6.78 (m, 1 H), 3.82 (s, 3 H), 2.40 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.7, 144.1, 139.5, 132.0, 129.1,
123.7, 122.9, 122.6, 120.6, 117.7, 117.3, 111.7, 110.9, 55.4, 9.5 ppm.
Conclusions
In conclusion, we have successfully developed an
iron(III)-catalyzed one-pot three-component cross-coupling HRMS (ESI): calcd. for C15H15N2O [M + H]+ 239.1179; found
239.1176.
nitration reaction of 2-aminopyridines, aldehydes, and
nitroalkane, giving rise to the straightforward formation of
imidazo[1,2-a]pyridine derivatives. Substrates that are com-
mercially available and an inexpensive and nonhazardous
catalyst are the highlights of this process. Various func-
tional groups are tolerated and proceed smoothly in moder-
ate to good yields.
2-(4-Methoxyphenyl)-3-methylimidazo[1,2-a]pyridine (4aeb): Yellow
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 6.8 Hz,
1
1 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.62 (dd, J = 9.2, J = 0.8 Hz, 1
H), 7.18–7.14 (m, 1 H), 7.01 (d, J = 8.4 Hz, 2 H), 6.83 (t, J =
6.8 Hz, 1 H), 3.86 (s, 3 H), 2.61 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.1, 144.2, 142.2, 129.5, 127.4, 123.4, 122.7, 117.2,
115.2, 114.0, 111.9, 55.3, 9.6 ppm. HRMS (ESI): calcd. for
C15H15N2O [M + H]+ 239.1179; found 239.1185.
Experimental Section
2-(3,4-Dimethoxyphenyl)-3-methylimidazo[1,2-a]pyridine
(4afb):
1
Yellow viscous oil. H NMR (400 MHz, CDCl3): δ = 7.89 (d, J =
6.8 Hz, 1 H), 7.66 (d, J = 9.2 Hz, 1 H), 7.44 (d, J = 2.0 Hz, 1 H),
7.27–7.25 (m, 1 H), 7.20–7.16 (m, 1 H), 6.96 (d, J = 8.0 Hz, 1 H),
6.86 (t, J = 6.8 Hz, 1 H), 3.99 (s, 3 H), 3.93 (s, 3 H), 2.63 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.1, 148.6, 144.1,
142.1, 127.5, 123.6, 122.7, 120.6, 117.1, 115.3, 112.1, 111.6, 111.0,
56.0, 55.9, 9.6 ppm. HRMS (ESI): calcd. for C16H17N2O2 [M +
H]+ 269.1285; found 269.1290.
General Remarks: Column chromatography was carried out with
silica gel. 1H NMR spectra were recorded at 400 MHz in CDCl3
and 13C NMR spectra were recorded at 100 MHz in CDCl3 by
using TMS as the internal standard. All new compounds were fur-
ther characterized by HRMS; copies of their 1H NMR and 13C
NMR spectra are provided. Commercially available reagents and
solvents were used without further purification.
Typical Procedure for the Preparation of 3-Methyl-2-arylimid-
azo[1,2-a]pyridine Derivatives: A test tube was charged with 1a
(0.5 mmol), 2a (0.6 mmol) and FeCl3 (8.13 mg, 0.05 mmol). Then
3b (10 equiv.) was added to the reaction system. The reaction was
stirred at 90 °C under air for 4 h. After cooling to room tempera-
ture, the solvent diluted with ethyl acetate (10 mL) was evaporated
in vacuo, and the residues were purified by column chroma-
tography (petroleum ether/EtOAc) to afford pure 4aab.
2-(2-Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (4agb): Yellow
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 6.8 Hz,
1
1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.58–7.56 (m, 1 H), 7.51–7.48 (m,
1 H), 7.37–7.32 (m, 2 H), 7.23–7.19 (m, 1 H), 6.91–6.87 (m, 1 H),
2.44 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.1, 140.3,
133.64, 133.56, 132.6, 129.7, 129.3, 126.6, 123.7, 122.9, 117.8,
117.6, 112.3, 9.7 ppm. HRMS (ESI): calcd. for C14H12ClN2 [M +
H]+ 243.0684; found 243.0681.
Characterization Data of 3-Methyl-2-arylimidazo[1,2-a]pyridine De-
2-(3-Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (4ahb): Yellow
solid, m.p. 133–135 °C. H NMR (400 MHz, CDCl3): δ = 7.91 (d,
rivatives 4
1
3-Methyl-2-phenylimidazo[1,2-a]pyridine (4aab): White solid, m.p.
144–146 °C. 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 6.8 Hz,
1 H), 7.79 (d, J = 7.2 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.47–
7.44 (m, 2 H), 7.35–7.32 (m, 1 H), 7.16–7.12 (m, 1 H), 6.81–6.78
(m, 1 H), 2.59 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.2, 142.3, 134.8, 128.4, 128.2, 127.2, 123.4, 122.7, 117.3, 115.8,
111.9, 9.5 ppm. HRMS (ESI): calcd. for C14H13N2 [M + H]+
209.1073; found 209.1075.
J = 6.8 Hz, 1 H), 7.82 (s, 1 H), 7.69–7.63 (m, 2 H), 7.41–7.38 (m,
1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.22–7.18 (m, 1 H), 6.89–6.86 (m,
1 H), 2.65 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.4,
141.0, 136.7, 134.5, 129.7, 128.3, 127.4, 126.3, 123.9, 122.9, 117.5,
116.3, 112.3, 9.6 ppm. HRMS (ESI): calcd. for C14H12ClN2 [M +
H]+ 243.0684; found 243.0685.
2-(4-Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (4aib): White so-
1
lid, m.p. 118–120 °C. H NMR (400 MHz, CDCl3): δ = 7.88 (d, J
3-Methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (4abb): Yellow viscous li-
= 7.2 Hz, 1 H), 7.72 (d, J = 6.8 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 1
H), 7.42 (d, J = 6.8 Hz, 2 H), 7.19–7.16 (m, 1 H), 6.84 (t, J =
6.8 Hz, 1 H), 2.61 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 144.4, 141.2, 133.3, 133.2, 129.5, 128.6, 123.7, 122.8, 117.4, 116.0,
112.2, 9.6 ppm. HRMS (ESI): calcd. for C14H12ClN2 [M + H]+
243.0684; found 243.0683.
1
quid. H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 6.8 Hz, 1 H),
7.69 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.28 (d, J =
8.0 Hz, 2 H), 7.18–7.14 (m, 1 H), 6.83 (td, J = 6.8, J = 1.2 Hz, 1
H), 2.63 (s, 3 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 144.3, 142.5, 137.1, 132.0, 129.2, 128.2, 123.3, 122.8, 117.4,
115.6, 111.9, 21.2, 9.6 ppm. HRMS (ESI): calcd. for C15H15N2 [M
+ H]+ 223.1230; found 223.1236.
2-(2-Bromophenyl)-3-methylimidazo[1,2-a]pyridine (4ajb): Yellow
1
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 6.8 Hz,
2-(3,4-Dimethylphenyl)-3-methylimidazo[1,2-a]pyridine (4acb): Yel-
low solid, m.p. 103–105 °C. 1H NMR (400 MHz, CDCl3): δ = 7.83
(d, J = 6.8 Hz, 1 H), 7.62 (d, J = 9.2 Hz, 2 H), 7.49 (dd, J = 7.6,
J = 1.6 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.15–7.10 (m, 1 H),
6.80–6.76 (m, 1 H), 2.59 (s, 3 H), 2.33 (s, 3 H), 2.30 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 144.1, 142.4, 136.7, 135.7, 132.3,
129.6, 129.5, 125.5, 123.2, 122.6, 117.2, 115.4, 111.8, 19.7, 19.5,
9.5 ppm. HRMS (ESI): calcd. for C16H17N2 [M + H]+ 237.1386;
found 237.1383.
1 H), 7.69–7.63 (m, 2 H), 7.51 (dd, J = 7.6, J = 1.6 Hz, 1 H), 7.40–
7.36 (m, 1 H), 7.28–7.22 (m, 1 H), 7.21–7.17 (m, 1 H), 6.87 (td, J
= 6.8, J = 0.8 Hz, 1 H), 2.42 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.9, 142.0, 138.3, 135.7, 132.7, 132.6, 129.4, 127.1,
123.8, 123.5, 122.9, 117.5, 112.1, 9.6 ppm. HRMS (ESI): calcd. for
C14H12BrN2 [M + H]+ 287.0178; found 287.0181.
2-(3-Bromophenyl)-3-methylimidazo[1,2-a]pyridine (4akb): Yellow
viscous oil. 1H NMR (400 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.91
2-(2-Methoxyphenyl)-3-methylimidazo[1,2-a]pyridine (4adb): Yellow (d, J = 7.2 Hz, 1 H), 7.72–7.70 (m, 1 H), 7.65–7.62 (m, 1 H), 7.49–
1
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 6.8 Hz,
7.46 (m, 1 H), 7.34–7.30 (m, 1 H), 7.22–7.18 (m, 1 H), 6.87 (td, J
1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.59–7.56 (m, 1 H), 7.38–7.34 (m, = 6.8, J = 1.2 Hz, 1 H), 2.64 (s, 3 H) ppm. 13C NMR (100 MHz,
1 H), 7.14–7.10 (m, 1 H), 7.08–7.04 (m, 1 H), 6.99 (d, J = 8.4 Hz, CDCl3): δ = 144.3, 140.7, 136.7, 131.1, 130.3, 129.99, 129.95, 126.8,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
One-Pot Synthesis of Imidazo[1,2-a]pyridines
124.0, 122.9, 122.6, 117.3, 112.3, 9.5 ppm. HRMS (ESI): calcd. for
C14H12BrN2 [M + H]+ 287.0178; found 287.0179.
3,8-Dimethyl-2-phenylimidazo[1,2-a]pyridine (4bab): Yellow viscous
oil. H NMR (400 MHz, CDCl3): δ = 7.80–7.78 (m, 2 H), 7.75 (d,
1
J = 6.8 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.35–7.32 (m, 1 H), 7.96 (d,
J = 6.8 Hz, 1 H), 6.75 (t, J = 6.8 Hz, 1 H), 2.66 (s, 3 H), 2.60 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.8, 142.0, 135.1,
128.5, 128.4, 127.3, 127.2, 122.3, 120.7, 116.2, 112.0, 17.1, 9.7 ppm.
HRMS (ESI): calcd. for C15H15N2 [M + H]+ 223.1230; found
223.1232.
2-(4-Bromophenyl)-3-methylimidazo[1,2-a]pyridine (4alb): Yellow
solid, m.p. 108–110 °C. H NMR (400 MHz, CDCl3): δ = 7.89 (d,
1
J = 7.2 Hz, 1 H), 7.69–7.67 (m, 2 H), 7.63 (d, J = 9.2 Hz, 1 H),
7.60–7.58 (m, 2 H), 7.21–7.17 (m, 1 H), 6.86 (td, J = 6.8, J =
0.8 Hz, 1 H), 2.62 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 144.4, 141.3, 133.8, 131.6, 129.8, 123.8, 122.9, 121.5, 117.4, 116.0,
112.2, 9.7 ppm. HRMS (ESI): calcd. for C14H12BrN2 [M + H]+
287.0178; found 287.0175.
3,7-Dimethyl-2-phenylimidazo[1,2-a]pyridine (4cab): White solid,
1
m.p. 173–175 °C. H NMR (400 MHz, CDCl3): δ = 7.78 (dd, J =
8.4 Hz, J = 1.2 Hz, 2 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.47–7.43 (m,
2 H), 7.37 (s, 1 H), 7.35–7.30 (m, 1 H), 6.65–6.63 (m, 1 H), 2.58 (s,
3 H), 2.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.7,
141.9, 135.0, 134.3, 128.4, 128.2, 127.1, 122.0, 115.7, 115.2, 114.5,
21.2, 9.5 ppm. HRMS (ESI): calcd. for C15H15N2 [M + H]+
223.1230; found 223.1226.
2-(2-Fluorophenyl)-3-methylimidazo[1,2-a]pyridine (4amb): Yellow
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.88–7.85 (m, 1 H),
1
7.76–7.72 (m, 1 H), 7.65–7.62 (m, 1 H), 7.38–7.31 (m, 1 H), 7.29–
7.22 (m, 1 H), 7.18–7.14 (m, 2 H), 6.83–6.79 (m, 1 H), 2.46 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.7, 158.3, 144.4,
137.1, 131.82 (d, J = 3.0 Hz), 129.2 (d, J = 9.0 Hz), 124.04 (d, J =
4.0 Hz), 123.3, 122.6, 117.8, 117.2, 115.6 (d, J = 22.0 Hz), 111.8,
9.05 (d, J = 6.0 Hz) ppm. HRMS (ESI): calcd. for C14H12FN2 [M
+ H]+ 227.0991; found 227.0986.
3,6-Dimethyl-2-phenylimidazo[1,2-a]pyridine (4dab): Yellow viscous
oil. 1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.0 Hz, 2 H),
7.61 (s, 1 H), 7.51 (d, J = 9.2 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H),
7.34–7.30 (m, 1 H), 6.98 (d, J = 9.2 Hz, 1 H), 2.55 (s, 3 H), 2.32
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.3, 142.1,
134.9, 128.3, 128.1, 127.1, 126.5, 121.4, 120.5, 116.6, 115.5, 18.3,
9.5 ppm. HRMS (ESI): calcd. for C15H15N2 [M + H]+ 223.1230;
found 223.1228.
3-Methyl-2-(naphthalen-1-yl)imidazo[1,2-a]pyridine (4anb): Yellow
1
viscous oil. H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.0 Hz,
1 H), 7.95 (d, J = 6.4 Hz, 1 H), 7.91–7.89 (m, 2 H), 7.70 (d, J =
9.2 Hz, 1 H), 7.60–7.53 (m, 2 H), 7.51–7.43 (m, 2 H), 7.26–7.20 (m,
1 H), 6.91–6.88 (m, 1 H), 2.43 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 144.4, 142.1, 133.8, 132.3, 132.2, 128.4, 128.3, 128.1,
126.4, 126.2, 125.7, 125.1, 123.4, 122.9, 117.7, 117.6, 112.0,
9.3 ppm. HRMS (ESI): calcd. for C18H15N2 [M + H]+ 259.1230;
found 259.1237.
3,5-Dimethyl-2-phenylimidazo[1,2-a]pyridine (4eab): Yellow viscous
oil. 1H NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 2 H), 7.47–
7.43 (m, 3 H), 7.37–7.33 (m, 1 H), 6.99 (dd, J = 8.8, J = 6.8 Hz, 1
H), 6.44 (d, J = 6.8 Hz, 1 H), 2.91 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 146.1, 143.9, 136.2, 134.9, 129.1, 128.3,
127.4, 124.1, 117.8, 115.9, 113.3, 20.8, 13.5 ppm. HRMS (ESI):
calcd. for C15H15N2 [M + H]+ 223.1230; found 223.1233.
2-(Furan-2-yl)-3-methylimidazo[1,2-a]pyridine (4aob): Yellow vis-
1
cous oil. H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 6.8 Hz, 1
H), 7.59 (d, J = 9.2 Hz, 1 H), 7.52 (d, J = 0.8 Hz, 1 H), 7.18–7.14
(m, 1 H), 6.87–6.81 (m, 2 H), 6.52 (q, J = 1.6 Hz, 1 H), 2.70 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.3, 144.5, 141.9,
138.5, 123.9, 122.7, 119.6, 117.2, 112.1, 111.3, 107.2, 9.1 ppm.
HRMS (ESI): calcd. for C12H11N2O [M + H]+ 199.0866; found
199.0870.
7-Chloro-3-methyl-2-phenylimidazo[1,2-a]pyridine (4fab): Pale-yel-
low solid, m.p. 124–126 °C. 1H NMR (400 MHz, CDCl3): δ = 7.75
(d, J = 8.0 Hz, 3 H), 7.60 (s, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.36–
7.32 (m, 1 H), 6.77 (dd, J = 7.2, J = 2.0 Hz, 1 H), 2.56 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 143.8, 143.1, 134.3, 129.9, 128.5,
128.2, 127.5, 123.0, 116.1, 116.0, 113.4, 9.5 ppm. HRMS (ESI):
calcd. for C14H12ClN2 [M + H]+ 243.0684; found 243.0688.
2-(2,4-Dichlorophenyl)-3-methylimidazo[1,2-a]pyridine (4apb): Yel-
low solid, m.p. 128–130 °C. 1H NMR (400 MHz, CDCl3): δ = 7.90
(d, J = 6.8 Hz, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.51–7.49 (m, 2 H),
7.33 (dd, J = 8.0, J = 2.0 Hz, 1 H), 7.22–7.17 (m, 1 H), 6.88–6.85
(m, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.1, 139.4, 134.23, 134.15, 133.3, 132.4, 129.3, 126.8, 123.5,
122.8, 117.8, 117.4, 112.1, 9.5 ppm. HRMS (ESI): calcd. for
C14H11Cl2N2 [M + H]+ 277.0294; found 277.0297.
6-Chloro-3-methyl-2-phenylimidazo[1,2-a]pyridine (4gab): Yellow
1
solid, m.p. 125–127 °C. H NMR (400 MHz, CDCl3): δ = 7.91 (s,
1 H), 7.78–7.76 (m, 2 H), 7.57 (dd, J = 9.6, J = 0.4 Hz, 1 H), 7.48–
7.44 (m, 2 H), 7.38–7.33 (m, 1 H), 7.14–7.11 (m, 1 H), 2.60 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.4, 142.5, 134.2,
128.5, 128.2, 127.6, 124.8, 120.7, 120.3, 117.7, 116.5, 9.6 ppm.
HRMS (ESI): calcd. for C14H12ClN2 [M + H]+ 243.0684; found
243.0678.
4-(3-Methylimidazo[1,2-a]pyridin-2-yl)benzonitrile (4aqb): Pale-yel-
low solid, m.p. 112–114 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92
(d, J = 8.4 Hz, 3 H), 7.74–7.72 (m, 2 H), 7.64–7.62 (m, 1 H), 7.25–
7.20 (m, 1 H), 6.89 (td, J = 6.8, J = 0.8 Hz, 1 H), 2.66 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 144.6, 140.3, 139.5, 132.2, 128.5,
124.3, 123.0, 119.0, 117.6, 117.2, 112.5, 110.5, 9.7 ppm. HRMS
(ESI): calcd. for C15H12N3 [M + H]+ 234.1026; found 234.1020.
6-Bromo-3-methyl-2-phenylimidazo[1,2-a]pyridine (4hab): Yellow so-
lid, m.p. 73–75 °C. 1H NMR (400 MHz, CDCl3): δ = 8.00 (s, 1 H),
7.76 (d, J = 7.6 Hz, 2 H), 7.51 (d, J = 9.6 Hz, 1 H), 7.46 (t, J =
7.6 Hz, 2 H), 7.37–7.33 (m, 1 H), 7.20 (dd, J = 9.2, J = 1.2 Hz, 1
H), 2.59 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.3,
142.7, 134.3, 128.5, 128.2, 127.6, 126.7, 123.0, 118.0, 116.3, 106.7,
9.6 ppm. HRMS (ESI): calcd. for C14H12BrN2 [M + H]+ 287.0178;
found 287.0173.
2-(2,6-Dimethylhept-5-en-1-yl)-3-methylimidazo[1,2-a]pyridine
1
(4arb): Yellow viscous oil. H NMR (400 MHz, CDCl3): δ = 7.79
(d, J = 6.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.11–7.07 (m, 1 H),
6.79–6.76 (m, 1 H), 5.10 (t, J = 6.8 Hz, 1 H), 2.76 (dd, J = 14.0, J
= 5.6 Hz, 1 H), 2.53 (dd, J = 13.6, J = 8.4 Hz, 1 H), 2.39 (s, 3 H),
6-Fluoro-3-methyl-2-phenylimidazo[1,2-a]pyridine (4iab): Yellow so-
1
2.09–1.98 (m, 3 H), 1.66 (s, 3 H), 1.59 (s, 3 H), 1.49–1.40 (m, 2 H), lid, m.p. 88–90 °C. H NMR (400 MHz, CDCl3): δ = 7.75 (d, J =
0.90 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 9.6 Hz, 3 H), 7.59–7.55 (m, 1 H), 7.46–7.42 (m, 2 H), 7.35–7.31 (m,
143.9, 143.0, 130.9, 124.9, 122.6, 122.4, 116.7, 115.9, 111.3, 37.1,
35.3, 33.8, 25.7, 25.6, 19.4, 17.6, 8.4 ppm. HRMS (ESI): calcd. for
C17H25N2 [M + H]+ 257.2012; found 257.2016.
1 H), 7.07–7.02 (m, 1 H), 2.55 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.4, 152.0, 143.8, 141.9, 134.4, 128.3 (d, J =
32.0 Hz), 127.4, 117.7 (d, J = 9.0 Hz), 117.3, 115.2 (d, J = 25.0 Hz),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
G. Huang et al.
FULL PAPER
109.4 (d,
J = 41.0 Hz), 9.6 ppm. HRMS (ESI): calcd. for 7.88 (s, 1 H), 7.86 (s, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.45 (dd, J =
C14H12FN2 [M + H]+ 227.0991; found 227.0997.
8.0, J = 0.8 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.22–7.18 (m, 1
H), 6.81 (td, J = 6.8, J = 0.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.7, 144.2, 135.8, 130.8, 130.2, 128.9, 125.7, 125.1,
124.5, 122.9, 117.6, 112.7, 108.5 ppm. HRMS (ESI): calcd. for
C13H10BrN2 [M + H]+ 273.0021; found 273.0018.
Ethyl-3-methyl-2-phenylimidazo[1,2-a]pyridine-7-carboxylate (4jab):
Yellow solid, m.p. 130–133 °C. H NMR (400 MHz, CDCl3): δ =
1
8.37 (s, 1 H), 7.86 (d, J = 6.8 Hz, 1 H), 7.79 (d, J = 7.2 Hz, 2 H),
7.48–7.45 (m, 2 H), 7.42–7.34 (m, 2 H), 4.40 (q, J = 7.2 Hz, 2 H),
2.62 (s, 3 H), 1.41 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.3, 145.1, 143.1, 134.1, 128.6, 128.2, 124.9, 122.0,
119.9, 119.6, 117.9, 111.4, 61.3, 13.9, 9.6 ppm. HRMS (ESI): calcd.
for C17H17N2O2 [M + H]+ 281.1285; found 281.1287.
2-(2-Fluorophenyl)imidazo[1,2-a]pyridine (4ama): Yellow solid, m.p.
1
80–82 °C. H NMR (400 MHz, CDCl3): δ = 8.31 (td, J = 7.6, J =
1.6 Hz, 1 H), 8.12 (d, J = 6.8 Hz, 1 H), 8.04 (d, J = 4.0 Hz, 1 H),
7.62 (d, J = 9.2 Hz, 1 H), 7.30–7.22 (m, 2 H), 7.20–7.12 (m, 2 H),
6.78 (t, J = 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
161.5, 159.0, 144.8, 139.0, 128.9 (d, J = 9.0 Hz), 128.7 (d, J =
3.0 Hz), 125.7, 125.0, 124.5 (d, J = 4.0 Hz), 117.3, 115.7, 115.5,
8-(Benzyloxy)-3-methyl-2-phenylimidazo[1,2-a]pyridine (4kab): Yel-
low viscous oil. 1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J =
7.2 Hz, 2 H), 7.50–7.48 (m, 3 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.38–
7.32 (m, 3 H), 7.30–7.25 (m, 1 H), 6.62 (t, J = 7.2 Hz, 1 H), 6.42
(d, J = 7.6 Hz, 1 H), 5.39 (s, 2 H), 2.57 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 147.8, 141.6, 138.9, 136.5, 134.8, 128.52,
128.48, 128.3, 127.9, 127.8, 127.1, 116.8, 116.0, 111.7, 102.4, 70.6,
9.8 ppm. HRMS (ESI): calcd. for C21H19N2O [M + H]+ 315.1492;
found 315.1494.
112.5 ppm. HRMS (ESI): calcd. for C13H10FN2 [M
213.0835; found 213.0837.
+
H]+
4-(Imidazo[1,2-a]pyridin-2-yl)benzonitrile (4aqa): Yellow solid, m.p.
146–148 °C. 1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 6.8 Hz,
1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.93 (s, 1 H), 7.68 (d, J = 8.0 Hz,
2 H), 7.60 (d, J = 9.2 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 6.83 (d,
J = 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.8,
143.4, 138.1, 132.4, 126.2, 125.8, 125.5, 119.0, 117.6, 113.0, 110.9,
109.5 ppm. HRMS (ESI): calcd. for C14H10N3 [M + H]+ 220.0869;
found 220.0874.
6-Bromo-3,5-dimethyl-2-phenylimidazo[1,2-a]pyridine (4lab): Yellow
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.66–7.64 (m, 2 H),
1
7.47–7.44 (m, 2 H), 7.38–7.31 (m, 2 H), 7.21 (d, J = 9.2 Hz, 1 H),
3.05 (s, 3 H), 2.89 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 145.1, 144.9, 134.5, 134.3, 129.2, 128.9, 128.2, 127.9, 127.8, 119.2,
109.3, 19.6, 14.5 ppm. HRMS (ESI): calcd. for C15H14BrN2 [M +
H]+ 301.0334; found 301.0340.
2-[4-(Methylthio)phenyl]imidazo[1,2-a]pyridine (4asa): Yellow solid,
m.p. 138–140 °C. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J =
6.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.82 (s, 1 H), 7.62 (d, J =
9.6 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 2 H), 7.18–7.14 (m, 1 H), 6.76
(td, J = 6.8, J = 0.8 Hz, 1 H), 2.52 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 145.7, 145.4, 138.2, 130.7, 126.8, 126.4,
125.5, 124.6, 117.4, 112.4, 107.8, 15.8 ppm. HRMS (ESI): calcd.
for C14H13N2S [M + H]+ 241.0794; found 241.0798.
Typical Procedure for the Preparation of 2-Arylimidazo[1,2-a]pyrid-
ine Derivatives: A test tube was charged with 1 (0.5 mmol), 2
(0.6 mmol), TBAI (0.5 mmol) and FeCl3 (8.13 mg, 0.05 mmol).
Then 3a (10 equiv. of MeNO2) was added to the reaction system.
The reaction was stirred at 90 °C under air for 4 h. After cooling
to room temperature, the solvent diluted with ethyl acetate (10 mL)
was evaporated in vacuo, and the residues were purified by column
chromatography (petroleum ether/EtOAc) to afford pure 4aaa.
8-Methyl-2-phenylimidazo[1,2-a]pyridine (4baa): Yellow viscous oil.
1H NMR (400 MHz, CDCl3): δ = 7.97–7.94 (m, 3 H), 7.81 (s, 1
H), 7.43 (t, J = 7.6 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 1 H), 6.93 (d, J
= 6.8 Hz, 1 H), 6.65 (t, J = 6.8 Hz, 1 H), 2.66 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 146.1, 145.1, 134.0, 128.6, 127.7,
127.5, 126.1, 123.4, 123.2, 112.3, 108.5, 17.1 ppm. HRMS (ESI):
calcd. for C14H13N2 [M + H]+ 209.1073; found 209.1068.
2-Phenylimidazo[1,2-a]pyridine (4aaa): White solid, m.p. 106–
108 °C. 1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 6.8 Hz, 1
H), 7.95 (d, J = 7.2 Hz, 2 H), 7.82 (s, 1 H), 7.62 (d, J = 9.2 Hz, 1
H), 7.43 (t, J = 7.6 Hz, 2 H), 7.34–7.30 (m, 1 H), 7.16–7.12 (m, 1
H), 6.74 (t, J = 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.7, 145.6, 133.7, 128.7, 127.9, 126.0, 125.5, 124.6, 117.4,
112.3, 108.1 ppm. HRMS (ESI): calcd. for C13H11N2 [M + H]+
195.0917; found 195.0921.
TypicalProcedureforthePreparationof3-Ethyl-2-arylimidazo[1,2-a]-
pyridine Derivatives: A test tube was charged with 1a (0.5 mmol), 2
(0.6 mmol) and FeCl3 (8.13 mg, 0.05 mmol). Then 3c (10 equiv. of
1-nitropropane) was added to the reaction system. The reaction
was stirred at 90 °C under air for 4 h. After cooling to room tem-
perature, the solvent diluted with ethyl acetate (10 mL) was evapo-
rated in vacuo, and the residues were purified by column
chromatography (petroleum ether/EtOAc) to afford pure 4aac.
2-(p-Tolyl)imidazo[1,2-a]pyridine (4aba): Yellow solid, m.p. 114–
116 °C. 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 6.8 Hz, 1
H), 7.85 (d, J = 8.0 Hz, 2 H), 7.81 (s, 1 H), 7.62 (d, J = 9.2 Hz, 1
H), 7.25 (d, J = 8.0 Hz, 2 H), 7.17–7.13 (m, 1 H), 6.75 (t, J =
6.8 Hz, 1 H), 2.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 145.9, 145.6, 137.8, 130.9, 129.4, 125.9, 125.5, 124.5, 117.4, 112.3,
107.7, 21.3 ppm. HRMS (ESI): calcd. for C14H13N2 [M + H]+
209.1073; found 209.1079.
3-Ethyl-2-phenylimidazo[1,2-a]pyridine (4aac): Yellow viscous oil.
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 6.8 Hz, 1 H), 7.80–
7.78 (m, 2 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.36–
7.33 (m, 1 H), 7.16–7.12 (m, 1 H), 6.79 (t, J = 6.8 Hz, 1 H), 3.09
(q, J = 7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.1, 141.4, 134.5, 128.4, 128.1, 127.4,
123.7, 122.8, 121.7, 117.4, 112.1, 16.9, 12.1 ppm. HRMS (ESI):
calcd. for C15H15N2 [M + H]+ 223.1230; found 223.1238.
2-(2-Methoxyphenyl)imidazo[1,2-a]pyridine (4ada): Yellow viscous
oil. 1H NMR (400 MHz, CDCl3): δ = 8.41 (dd, J = 7.6, J = 1.6 Hz,
1 H), 8.16 (s, 1 H), 8.06 (d, J = 6.8 Hz, 1 H), 7.61–7.59 (m, 1 H),
7.32–7.27 (m, 1 H), 7.13–7.08 (m, 2 H), 6.97 (d, J = 8.4 Hz, 1 H),
6.69 (t, J = 6.8 Hz, 1 H), 3.95 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.6, 144.2, 140.9, 128.6, 128.5, 125.5, 124.4, 122.1,
120.8, 117.0, 112.4, 111.8, 110.7, 55.2 ppm. HRMS (ESI): calcd.
for C14H13N2O [M + H]+ 225.1023; found 225.1026.
3-Ethyl-2-(p-tolyl)imidazo[1,2-a]pyridine (4abc): Yellow viscous oil.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 6.8 Hz, 1 H), 7.68
(d, J = 8.4 Hz, 2 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.29–7.27 (m, 2 H),
7.18–7.12 (m, 1 H), 6.81 (td, J = 6.8, J = 0.8 Hz, 1 H), 3.10 (q, J
= 7.6 Hz, 2 H), 2.41 (s, 3 H), 1.35 (t, J = 7.6 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 144.2, 141.8, 137.1, 131.8, 129.2,
128.0, 123.5, 122.8, 121.4, 117.5, 111.9, 21.2, 17.0, 12.2 ppm.
2-(3-Bromophenyl)imidazo[1,2-a]pyridine (4aka): Yellow solid, m.p.
104–106 °C. 1H NMR (400 MHz, CDCl3): δ = 8.13–8.12 (m, 2 H),
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
One-Pot Synthesis of Imidazo[1,2-a]pyridines
HRMS (ESI): calcd. for C16H17N2 [M + H]+ 237.1386; found
237.1381.
Acknowledgments
The authors are grateful for financial support by the Fundamental
Research Funds for the Central Universities, P. R. China.
3-Ethyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (4aec): Yellow
viscous oil. H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 6.8 Hz,
1
1 H), 7.72 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.16–
7.12 (m, 1 H), 7.00 (d, J = 8.8 Hz, 2 H), 6.80 (t, J = 6.8 Hz, 1 H),
3.85 (s, 3 H), 3.07 (q, J = 7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 144.1, 141.5,
129.2, 127.3, 123.3, 122.7, 121.0, 117.3, 113.9, 111.8, 55.2, 17.0,
12.1 ppm. HRMS (ESI): calcd. for C16H17N2O [M + H]+ 253.1336;
found 253.1334.
[1] a) S. Maiti, S. Biswas, U. Jana, J. Org. Chem. 2010, 75, 1674–
1683; b) A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39,
3168–3210; Angew. Chem. 2000, 112, 3300–3344; c) A.
Dömling, Chem. Rev. 2006, 106, 17–89; d) H. Yoshida, H. Fu-
kushima, J. Ohshita, A. Kunai, J. Am. Chem. Soc. 2006, 128,
11040–11041; e) H. Yoshida, T. Morishita, H. Fukushima, J.
Ohshita, A. Kunai, Org. Lett. 2007, 9, 3367–3370; f) H. Yosh-
ida, T. Morishita, J. Ohshita, Org. Lett. 2008, 10, 3845–3847;
g) X. F. Lin, Z. J. Mao, X. X. Dai, P. Lu, Y. G. Wang, Chem.
Commun. 2011, 47, 6620–6622; h) D. Bonne, M. Dekhane, J. P.
Zhu, Angew. Chem. Int. Ed. 2007, 46, 2485–2488; Angew.
Chem. 2007, 119, 2537–2540; i) M. M. Heravi, S. Sadjadi,
H. A. Oskooie, R. H. Shoar, F. F. Bamoharram, Tetrahedron
Lett. 2009, 50, 662–666.
2-(3,4-Dimethoxyphenyl)-3-ethylimidazo[1,2-a]pyridine (4afc): Yel-
low viscous oil. 1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J =
6.8 Hz, 1 H), 7.66 (d, J = 9.2 Hz, 1 H), 7.42 (d, J = 1.6 Hz, 1 H),
7.26–7.23 (m, 1 H), 7.19–7.15 (m, 1 H), 6.96 (d, J = 8.0 Hz, 1 H),
6.84 (t, J = 6.8 Hz, 1 H), 3.97 (s, 3 H), 3.94 (s, 3 H), 3.10 (q, J =
7.6 Hz, 2 H), 1.36 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.0, 148.5, 144.1, 141.5, 127.5, 123.6, 122.7, 121.2,
120.2, 117.3, 112.0, 111.4, 110.9, 55.82, 55.80, 17.0, 12.1 ppm.
HRMS (ESI): calcd. for C17H19N2O2 [M + H]+ 283.1441; found
283.1448.
[2] G. H. Posner, Chem. Rev. 1986, 86, 831–844.
[3] a) K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth,
D. E. Cavender, G. C. Olini, B. Fahmy, J. Siekierka, Bioorg.
Med. Chem. Lett. 2003, 13, 347–350; b) G. C. Moraski, L. D.
Markley, P. A. Hipskind, H. Boshoff, S. Cho, S. G. Franzblau,
M. J. Miller, ACS Med. Chem. Lett. 2011, 2, 466–470.
[4] J. S. Bae, D. W. Lee, D. H. Lee, D. S. Jeong, PCT Int. Appl
WO2007011163A1, 2007.
[5] N. Hsua, S. K. Jha, T. Coleman, M. G. Frank, Behav. Brain
Res. 2009, 201, 233–236.
[6] E. C. Gueiffier, A. Gueiffier, Mini-Rev. Med. Chem. 2007, 7,
888–899.
2-(4-Chlorophenyl)-3-ethylimidazo[1,2-a]pyridine (4aic): Yellow so-
1
lid, m.p. 100–102 °C. H NMR (400 MHz, CDCl3): δ = 7.93 (d, J
= 6.8 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 9.2 Hz, 1
H), 7.42 (d, J = 8.8 Hz, 2 H), 7.19–7.15 (m, 1 H), 6.82 (t, J =
6.8 Hz, 1 H), 3.06 (q, J = 7.6 Hz, 2 H), 1.33 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.3, 140.5, 133.3,
133.2, 129.2, 128.6, 123.8, 122.8, 121.8, 117.5, 112.1, 16.9,
12.1 ppm. HRMS (ESI): calcd. for C15H14ClN2 [M + H]+ 257.0840;
found 257.0845.
[7] a) A. R. Katritzky, Y. J. Xu, H. Tu, J. Org. Chem. 2003, 68,
4935–4937; b) T. S. Harrison, G. M. Keating, CNS Drugs 2005,
19, 65–89.
[8] S. M. Hanson, E. V. Morlock, K. A. Satyshur, C. Czajkowski,
J. Med. Chem. 2008, 51, 7243–7252.
[9] A. N. Jain, J. Med. Chem. 2004, 47, 947–961.
2-(2-Bromophenyl)-3-ethylimidazo[1,2-a]pyridine (4ajc): Yellow so-
lid, m.p. 76–78 °C. H NMR (400 MHz, CDCl3): δ = 7.96 (d, J =
1
6.8 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.45 (dd, J = 7.6, J = 1.2 Hz, 1
H), 7.36 (td, J = 7.6, J = 1.2 Hz, 1 H), 7.25–7.21 (m, 1 H), 7.17–
7.13 (m, 1 H), 6.81 (td, J = 6.8, J = 1.2 Hz, 1 H), 2.87 (q, J =
7.6 Hz, 2 H), 1.17 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.8, 141.5, 136.0, 132.5, 132.2, 129.3, 126.8, 124.0,
123.3, 123.0, 122.7, 117.7, 111.9, 16.8, 11.6 ppm. HRMS (ESI):
calcd. for C15H14BrN2 [M + H]+ 301.0334; found 301.0337.
[10] S. Z. Langer, S. Arbilla, J. Benavides, B. Scatton, Adv. Biochem.
Psychopharmacol. 1990, 46, 61–72.
[11] a) C. J. R. Fookes, T. Q. Pham, F. Mattner, I. Greguric, C.
LocЈh, X. Liu, P. Berghofer, R. Shepherd, M. C. Gregoire, A.
Katsifis, J. Med. Chem. 2008, 51, 3700–3712; b) O. Barun, H.
Ila, H. Junjappa, J. Org. Chem. 2000, 65, 1583–1587; c) G. Tra-
pani, V. Laquintana, N. Denora, A. Trapani, A. Lopedota, A.
Latrofa, M. Franco, M. Serra, M. G. Pisu, I. Floris, E. Sanna,
G. Biggio, G. Liso, J. Med. Chem. 2005, 48, 292–305; d) K. T. J.
Loones, B. U. W. Maes, C. Meyers, J. Deruytter, J. Org. Chem.
2006, 71, 260–264; e) B. Yan, Y. Liu, Org. Lett. 2007, 9, 3433–
3436; f) N. Denora, V. Laquintana, M. G. Pisu, R. Dore, L.
Murru, A. Latrofa, G. Trapani, E. Sanna, J. Med. Chem. 2008,
51, 6876–6888; g) T. Masquelin, H. Bui, B. Brickley, G. Ste-
phenson, J. Schwerkosked, C. Hulmea, Tetrahedron Lett. 2006,
47, 2989–2991; h) D. Basavaiah, B. Devendar, D. V. Lenin, T.
Satyarayana, Synlett 2009, 411–416; i) V. Laquintana, N. De-
nora, A. Lopedota, H. Suzuki, M. Sawada, M. Serra, G.
Biggio, A. Latrofa, G. Trapani, G. Liso, Bioconjugate Chem.
2007, 18, 1397–1407; j) N. Chernyak, V. Gevorgyan, Angew.
Chem. Int. Ed. 2010, 49, 2743–2746; Angew. Chem. 2010, 122,
2803–2806; k) S. K. Guchait, A. L. Changude, G. Priyadarsh-
ani, J. Org. Chem. 2012, 77, 4438–4444; l) D. K. Nair, S. M.
Mobin, N. N. Namboothiri, Org. Lett. 2012, 14, 4580–4583; m)
D. P. Mohan, S. N. Rao, S. Adimurthy, J. Org. Chem. 2013, 78,
1266–1272; n) O. A. Attanasi, L. Bianchi, L. A. Campisi, L.
De Crescentini, G. Favi, F. Mantellini, Org. Lett. 2013, 15,
3646–3649.
3-Ethyl-2-(2-fluorophenyl)imidazo[1,2-a]pyridine (4amc): Yellow vis-
1
cous oil. H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 7.2 Hz, 1
H), 7.71–7.63 (m, 2 H), 7.37–7.32 (m, 1 H), 7.26–7.22 (m, 1 H),
7.18–7.13 (m, 2 H), 6.82–6.79 (m, 1 H), 2.94 (q, J = 7.6 Hz, 2 H),
1.26 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
160.9, 158.5, 144.5, 136.4, 132.0 (d, J = 3.0 Hz), 129.3 (d, J =
8.0 Hz), 124.1 (d, J = 3.0 Hz), 123.4 (d, J = 5.0 Hz), 123.0, 117.6,
115.7, 115.5, 111.9, 16.9, 11.5 ppm. HRMS (ESI): calcd. for
C15H14FN2 [M + H]+ 241.1148; found 241.1144.
4-(3-Ethylimidazo[1,2-a]pyridin-2-yl)benzonitrile (4aqc): Yellow so-
1
lid, m.p. 158–160 °C. H NMR (400 MHz, CDCl3): δ = 7.98 (d, J
= 6.8 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2
H), 7.63 (d, J = 9.2 Hz, 1 H), 7.24–7.21 (m, 1 H), 6.89 (t, J =
6.8 Hz, 1 H), 3.12 (q, J = 7.6 Hz, 2 H), 1.38 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.5, 139.6, 139.5,
132.2, 128.3, 124.4, 123.1, 122.9, 119.0, 117.8, 112.5, 110.5, 17.0,
12.1 ppm. HRMS (ESI): calcd. for C16H14N3 [M + H]+ 248.1182;
found 248.1185.
[12] a) C. Enguehard, J. L. Renou, V. Collot, M. Hervet, S. Rault,
A. Gueiffier, J. Org. Chem. 2000, 65, 6572–6575; b) J. Kouba-
chi, S. E. Kazzouli, S. B. Raboin, A. Mouaddib, G. Guillaumet,
J. Org. Chem. 2007, 72, 7650–7655; c) S. Marhadour, M. A.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of the products.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
G. Huang et al.
FULL PAPER
Bazin, P. Marchand, Tetrahedron Lett. 2012, 53, 297–300; d)
A. K. Bagdi, M. Rahman, S. Santra, A. Majee, A. Hajra, Adv.
Synth. Catal. 2013, 355, 1741–1747.
[17]
[18]
a) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev. 2004,
104, 6217–6254; b) B. D. Sherry, A. Fürstner, Acc. Chem. Res.
2008, 41, 1500–1511.
a) S. Santra, A. K. Bagdi, A. Majee, A. Hajra, Adv. Synth.
Catal. 2013, 355, 1065–1070; b) X. Liu, D. Wang, B. Chen,
Tetrahedron 2013, 69, 9417–9421; c) X. Liu, D. Wang, Y. Chen,
D. Tang, B. Chen, Adv. Synth. Catal. 2013, 355, 2798–2802.
a) H. Yan, R. Yan, S. Yang, X. Gao, Y. Wang, G. Huang, Y.
Liang, Chem. Asian J. 2012, 7, 2028–2031; b) R. L. Yan, H.
Yan, C. Ma, Z. Y. Ren, X. A. Gao, G. S. Huang, Y. M. Liang,
J. Org. Chem. 2012, 77, 2024–2028.
[13] a) W. X. Dai, J. L. Petersen, K. K. Wang, J. Org. Chem. 2005,
70, 6647–6652; b) E. F. DiMauro, J. M. Kennedy, J. Org. Chem.
2007, 72, 1013–1016; c) H. Wang, Y. Wang, C. Peng, J. Zhang,
Q. Zhu, J. Am. Chem. Soc. 2010, 132, 13217–13219; d) K. S.
Masters, T. R. M. Rauws, A. K. Yadav, W. A. Herrebout, B. V.
Veken, B. U. W. Maes, Chem. Eur. J. 2011, 17, 6315–6320; e)
H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang, Q. Zhu, Angew.
Chem. Int. Ed. 2011, 50, 5678–5681; Angew. Chem. 2011, 123,
5796–5799.
[19]
[20] C. He, J. Hao, H. Xu, Y. Mo, H. Liu, J. Han, A. Lei, Chem.
Commun. 2012, 48, 11073–11075.
[21] H. Shiraishi, T. Nishitani, S. Sakaguchi, Y. Ishii, J. Org. Chem.
1998, 63, 6234–6238.
[14] A. J. Stasyuk, M. Banasiewicz, M. K. Cyran´ski, D. T. Gryko,
J. Org. Chem. 2012, 77, 5552–5558.
[15] M. Adib, E. Sheikhi, N. Rezaei, Tetrahedron Lett. 2011, 52,
3191.
Received: November 5, 2013
[16] a) H. Yan, S. Z. Yang, X. A. Gao, K. Zhou, C. Ma, R. L. Yan,
G. S. Huang, Synlett 2012, 23, 2961–2964.
Published Online: ᭿
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31658
/KAP1
Date: 10-03-14 17:00:15
Pages: 11
One-Pot Synthesis of Imidazo[1,2-a]pyridines
Nitrogen Heterocycles
H. Yan, Y. Wang, C. Pan, H. Zhang,
S. Yang, X. Ren, J. Li,
G. Huang* ...................................... 1–11
Iron(III)-Catalyzed Denitration Reaction:
One-Pot Three-Component Synthesis of
Imidazo[1,2-a]pyridine Derivatives
An iron(III)-catalyzed one-pot three-com-
ponent cross-coupling nitration reaction of
2-aminopyridines, aldehydes, and nitro-
alkane, leading to the straightforward for-
mation of imidazo[1,2-a]pyridine deriva-
tives has been reported. In this procedure,
the starting materials are commercially
available. The system shows good func-
tional-group tolerance and proceeds
smoothly in moderate to good yields.
Keywords: Synthetic methods / Multicom-
ponent reactions / Nitrogen heterocycles /
Iron
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11