Simple and efficient one-pot synthesis of imidazo[1,2-a]pyridines catalyzed by magnetic nano-Fe3O4-KHSO4·SiO 2

Article abstract of DOI:10.1055/s-0032-1317323

The present report highlights a magnetic nano-Fe₃O ₄-KHSO₄·SiO₂ catalyzed synthesis of imidazo[1,2-a]pyridines. The synthetic strategy adopted is expedient, versatile, and offers good to excellent yields from readily available starting materials.

Full text of DOI:10.1055/s-0032-1317323

LETTER
▌2635
lSetitemr ple and Efficient One-Pot Synthesis of Imidazo[1,2-a]pyridines Catalyzed
by Magnetic Nano-Fe3O4–KHSO4·SiO2
Synthesis of Imidazo[1,2-a]pyridines
Tirumaleswararao Guntreddi, Bharat Kumar Allam, Krishna Nand Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
Fax +91(542)2368127; E-mail: knsingh@bhu.ac.in
Received: 04.08.2012; Accepted after revision: 05.09.2012
there is no report on iron-catalyzed synthesis of imid-
Abstract: The present report highlights a magnetic nano-Fe3O4–
azo[1,2-a]pyridines. In context of the above and as a part
KHSO4·SiO2 catalyzed synthesis of imidazo[1,2-a]pyridines. The
of our current research interest,7 we report herein a facile
synthetic strategy adopted is expedient, versatile, and offers good to
and straightforward synthesis of imidazo[1,2-a]pyridines
by a magnetic nano-Fe3O4–KHSO4·SiO2 catalyzed one-
pot three-component reaction of 2-aminopyridine, alde-
hyde, and alkyne (Scheme 1).
excellent yields from readily available starting materials.
Key words: multicomponent reactions, transition metals, hetero-
cycles, heterogeneous catalysis, iron
N
Multi-component reactions (MCRs) constitute one of the
most promising synthetic strategies, that have trans-
formed the art of organic synthesis.1 Due to their conver-
gent nature and high bond-forming index (BFI), these
reactions are capable of constructing a synthetic hub of di-
vergent molecules in an efficient fashion.2 Of special in-
terest are compounds which possess the molecular
skeleton found in natural products and drug-like mole-
cules.3 Since the vast majority of natural products and
drug-like compounds possess heterocyclic subunits, the
ability to synthesize diverse heterocyclic compounds effi-
ciently is critical. Imidazo[1,2-a]pyridines are important
fused heterocycles due to their potential biological activi-
ties. They have been used for the treatment of septic acute
lung injury (ALI), osteoporosis, and are extensively em-
ployed as PI3Kα inhibitors, mGlu2 receptors, anti-viral,
anti-cancer, anxyolytic, and anti-herpes drugs (Figure 1).4
CF3
N
Cl
N
N
HN
O
N
CN
H
Cl
mGlu2 receptor
olprinone
(drug for the treatment of acute lung injury)
OMe
OMe
SO2R
HN
O
COOEt
N
N
N
CF3
N
N
anti-cancer agent
PI3Kα inhibitor
Different methods have been applied for the synthesis of
imidazo[1,2-a]pyridines. Among these, only a few reports
deal with the one-pot synthesis of imidazo[1,2-a]pyridine
scaffolds employing different catalytic systems.5 Thus,
there is scope for developing operationally simple and ef-
ficient synthetic strategies. Magnetic Fe3O4 nanoparticles
have recently emerged as an attractive catalyst for various
synthetic transformations because of their easy recyclabil-
ity, reusability, high surface area, low toxicity, and excel-
lent activity.6 An up-to-date literature survey reveals that
Figure 1 Biologically active imidazo[1,2-a]pyridine derivatives
In order to achieve a practical protocol for the one-pot
synthesis of imidazo[1,2-a]pyridines, the effect of a num-
ber of parameters such as catalysts, additives, and solvents
was screened for the model reaction employing 2-amino-
pyridine (1), benzaldehyde (2a), and phenylacetylene
(3a).8 The results are presented in Table 1.
N
O
magnetic nano-Fe3O4–KHSO4⋅SiO2
R1
R2
3a,b
+
+
R1
N
110 °C, toluene, 17–24 h
N
NH2
1
2a–o
4a–o
R2
R1 = alkyl, aryl
R2 = aryl, alkyl
Scheme 1 One-pot synthesis of imidazo[1,2-a]pyridines
SYNLETT 2012, 23, 2635–2638
Advanced online publication: 01.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317323; Art ID: ST-2012-D0659
© Georg Thieme Verlag Stuttgart · New York

2636
T. Guntreddi et al.
LETTER
Table 1 Screening of Reaction Conditionsa
use of additives and solvents, which conclusively provid-
ed Fe3O4–KHSO4·SiO2 in toluene as the best combination
(entry 14).9 The KHSO4·SiO2 additive is assumed to pro-
mote the formation of imine considerably to facilitate nu-
cleophilic attack of the C–H activated phenylacetylene to
the intermediate imine. The propargylamine, thus formed,
subsequently underwent nano-Fe3O4 catalyzed 5-exo-dig
cyclization. Other additives such as L-proline, K-10, and
P2O5 did not improve the yield (entries 17–19).
Entry Catalyst (mol%)
Additive
Solvent
Yield
(%)b
1
2
CdI2 (10)
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
trace
23
–
CdI2 (10)
Et3N
3
ZrOCl2·8H2O (10)
SbCl5 (10)
–
4
–
–
With the optimized conditions in hand, the scope of this
methodology was extended to the reaction of a wide range
of aldehydes and alkynes with 2-aminopyridine to afford
a variety of imidazo[1,2-a]pyridines (Table 2). The find-
ings revealed that a range of reactant combinations afford-
ed good to excellent product yield, except the
combination of 2-aminopyridine, 4-(dimethylami-
no)benzaldehyde, and phenylacetylene which led to no
product (entry 8), possibly due to the coordination of the
NMe2 group with Fe3O4. Among the aromatic aldehydes,
benzaldehyde and halo-substituted benzaldehydes
showed excellent reactivity in this cyclization (entries 1–
6); whereas those bearing strong electron-donating and
electron-withdrawing groups showed appreciable lower-
ing of yield (entries 7, 10, 11 and 14). The reaction was
also feasible with an aliphatic aldehyde, but it required an
excess of KHSO4·SiO2 (entry 12). Furfural, a representa-
tive heterocyclic aldehyde, also participated in the reac-
tion with reasonably good yield (entry 13). It is worth
mentioning that the nano-Fe3O4 could be magnetically re-
covered by an external magnetic field and could be reused
six times without significant loss of activity (Figure 2).10
5
NiCl2·6H2O (10)
TiO2 (10)
–
–
6
–
–
7
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Fe3O4 (5)
–
32
35
8
Et3N
9
–
BMIM[BF4] 30
10
11
12
13
14
15
16
17
18
19
TFA
toluene
toluene
toluene
toluene
40
43
57
57
89
78
72
59
68
64
–
–
–
Fe3O4 (10)
Fe3O4 (12)
Fe3O4 (10)
Fe3O4 (10)
KHSO4·SiO2 toluene
KHSO4·SiO2 PhCl
NaHSO4·SiO2 toluene
Fe3O4 (10)
Fe3O4 (10)
L-proline
K-10
toluene
toluene
toluene
Fe3O4 (10)
Fe3O4 (10)
P2O5
In conclusion, we have demonstrated the catalytic use of
magnetic nano-Fe3O4–KHSO4·SiO2 for an efficient one-
pot synthesis of imidazo[1,2-a]pyridines. The approach is
convenient, practical, versatile, and may be used as an al-
ternative to the existing synthetic methodologies.
a Using 1 (1 mmol), 2a (1 mmol), 3a (1.2 mmol) at 110 °C for 24 h.
b Isolated yield after column chromatography.
The investigation was initiated by examining the effect of
various unexplored catalysts for the aforementioned mod-
el reaction. Out of all the trials, ZrOCl2·8H2O, SbCl5,
NiCl2·6H2O, and TiO2 did not result in the formation of
the product (entries 3–6). CdI2 alone produced only a trace
of the product, although a CdI2–Et3N combination
brought about 23% product yield (entries 1 and 2).
Yb(OTf)3, Yb(OTf)3–Et3N, and Yb(OTf)3–TFA afforded
lower yields (entries 7, 8 and 10); nevertheless an
Yb(OTf)3–[BMIM][BF4] combination resulted in 30%
yield (entry 9). Nano-Fe3O4 (10 mol%) notably gave the
product in 57% yield (entry 12). Further increase in the
catalyst mol% did not improve the yield (entry 13). The
amino–imino tautomerism in 2-aminopyridine and the
soft acidic centers of nano-iron did not appear to favor for-
mation of imine, which may be the reason for low yields
obtained in the presence of nano-Fe3O4 alone. To achieve
increased conversion, attention was directed towards the
Figure 2 Recyclability of nano-Fe3O4
Synlett 2012, 23, 2635–2638
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Imidazo[1,2-a]pyridines
2637
Table 2 One-Pot Three-Component Coupling of 2-Amino Pyridine, Aldehyde, and Alkynea
Entry Aldehyde 2
Alkyne 3
Product 4
Time (h) Yield (%)b
1
2a
3a
4a
24
89
N
Ph
Ph
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
2
3
2b
2c
2d
2e
2f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
4b
4c
4d
4e
4f
20
20
20
20
20
24
24
20
24
24
17
17
24
86
84
83
82
83
75
n.r.
79
69
65
70c
72
55
4-ClC6H4
Ph
O
O
3-ClC6H4
Ph
Cl
Br
4
4-BrC6H4
Ph
O
O
5
3-BrC6H4
Ph
Br
Br
6
2-BrC6H4
Ph
O
MeO
7
2g
2h
2i
4g
4h
4i
4-MeOC6H4
Ph
O
Me2N
8
4-Me2NC6H4
Ph
O
9
4-MeC6H4
Ph
O
O2N
10
11
12
13
14
2j
4j
4-O2NC6H4
Ph
O
NO2
O
2k
2l
4k
4l
2-O2NC6H4
Ph
O
Ph
Ph
Ph
O
2m
2n
4m
4n
O
O
HO
OH
OMe
O
MeO
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2635–2638

2638
T. Guntreddi et al.
LETTER
Table 2 One-Pot Three-Component Coupling of 2-Amino Pyridine, Aldehyde, and Alkynea (continued)
Entry Aldehyde 2
Alkyne 3
Product 4
Time (h) Yield (%)b
15
2o
3b
4o
20
82
Hex
N
Ph
O
N
Hex
a Using 1 (1 mmol), 2 (1 mmol), 3 (1.2 mmol), nano-Fe3O4 (0.1 mmol) and KHSO4·SiO2 (150 mg) at 110 °C in anhyd toluene.
b Isolated yield after column chromatography.
c Using KHSO4·SiO2 (175 mg).
(c) Singh, N.; Singh, S. K.; Khanna, R. S.; Singh, K. N.
Tetrahedron Lett. 2011, 52, 2419. (d) Kumari, K.;
Raghuvanshi, D. S.; Jouikov, V.; Singh, K. N. Tetrahedron
Lett. 2012, 53, 1130. (e) Raghuvanshi, D. S.; Singh, K. N.
Tetrahedron Lett. 2011, 52, 5702. (f) Raghuvanshi, D. S.;
Singh, K. N. Synlett 2011, 373.
Acknowledgement
We thank the Council of Scientific and Industrial Research (CSIR),
New Delhi for financial assistance.
References
(8) General Experimental Procedure: To an oven-dried 25
mL round-bottom flask containing a magnetic stir bar was
added 2-aminopyridine (1 mmol, 94.1 mg), aldehyde (1
mmol), KHSO4·SiO2 (150 mg, 0.032 mmol with respect to
KHSO4), and anhyd toluene (2 mL). The mixture was stirred
for 15 min and to it was then added alkyne (1.2 mmol) and
nano-Fe3O4 [<50 nm particle size, ≥98% trace metals basis
(Aldrich)] (0.1 mmol, 23.2 mg). The total reaction mixture
was refluxed at 110 °C for the appropriate time. After
completion of the reaction (monitored by TLC), EtOAc was
added (10 mL), the magnetic Fe3O4 nanoparticles were
collected on the magnetic stir bar, and the mixture was
filtered through a porous plug. The filtrate was concentrated
under reduced pressure and the crude product thus obtained,
was purified by silica gel column chromatography (EtOAc–
hexane, 1:9). The pure products were characterized based
upon their physical and spectroscopic properties.
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Spectroscopic Data of the Representative Compounds:
3-Benzyl-2-(3-chlorophenyl)imidazo[1,2-a]pyridine (4c):
White solid; mp = 141–142 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.77 (s, 1 H), 7.65–7.53 (m, 3 H), 7.27–7.22 (m,
4 H), 7.21–7.10 (m, 2 H), 7.07 (d, J = 6.6 Hz, 2 H), 6.68–
6.64 (m, 1 H), 4.42 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 143.7, 142.2, 136.1, 135.9, 134.4, 132.0, 129.9,
129.6, 129.3, 128.1, 127.9, 127.7, 126.9, 126.3, 124.8,
123.3, 118.0, 117.7, 112.4, 29.9 ppm.
3-Benzyl-2-(4-tolyl)imidazo[1,2-a]pyridine (4i): Pale
yellow solid; mp = 160–161 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.69 (t, J = 8.1 Hz, 4 H), 7.26 (br s, 5 H), 7.16–
7.13 (m, 3 H), 6.70 (br s, 1 H), 4.49 (s, 2 H), 2.39 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 144.6, 144.0, 137.7,
136.6, 131.9, 129.0, 128.9, 128.2, 127.6, 126.7, 124.1,
123.1, 117.5, 117.3, 112.0, 30.1, 21.1 ppm.
(9) For the preparation of KHSO4·SiO2, see: Goswami, N.; Das,
R. N.; Borthakur, N. Ind. J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2007, 46, 1893.
(10) Reusability of magnetic nano-Fe3O4: After completion of the
reaction EtOAc was added and the Fe3O4-nanoparticles were
recovered by the application of an external magnet. The
recovered nanoparticles were thoroughly washed with Et2O,
dried at 130 °C for 1 h and then reused for a new catalytic
cycle.
(7) (a) Allam, B. K.; Singh, K. N. Tetrahedron Lett. 2011, 52,
5851. (b) Allam, B. K.; Singh, K. N. Synthesis 2011, 1125.
Synlett 2012, 23, 2635–2638
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