Organic reactions in ionic liquids: Ionic liquid-accelerated cyclocondensation of α-tosyloxyketones with 2-aminopyridine

Article abstract of DOI:10.1055/s-2002-33330

The room temperature ionic liquid n-butylpyridinium tetrafluoroborate (BPyBF₄) is used as a 'green' recyclable alternative to classical molecular solvents for the cyclocondensation of α-tosyloxyketones with 2-aminopyridine. Significant rate enh

Full text of DOI:10.1055/s-2002-33330

PAPER
1505
Organic Reactions in Ionic Liquids: Ionic Liquid-Accelerated
Cyclocondensation of -Tosyloxyketones with 2-Aminopyridine
C
yclocondensation
u
R
eactions
i
a
Ionic Liq
n
a
Ningbo Institute of Technology, Zhejiang University, Ningbo, 315104, P. R. China
b
Department of Chemistry, Zhejiang University (Xi-Xi campus), Hangzhou, 310028, P. R. China
E-mail: zhenchuc@mail.hz.zj.cn
c
Pharmaceutical Sciences Research Institute, Aston University, Aston Triangle, Birmingham B4 7ET, UK
Received 6 February 2002; revised 30 April 2002
hexafluorophosphorate (BMImPF6) were synthesized ac-
cording to the procedures reported in the literature.21
Abstract: The room temperature ionic liquid n-butylpyridinium
tetrafluoroborate (BPyBF4) is used as a ‘green’ recyclable alterna-
tive to classical molecular solvents for the cyclocondensation of
tosyloxyketones with 2-aminopyridine. Significant rate enhance-
ments and improved yields have been observed.
-
First, we examined the efficacy of different ionic liquids
in the cyclocondensations of -tosyloxyacetophenone
(1a) with 2-aminopyridine (2) (Scheme 1, Table 1). The
results summarized in Table 1 show that BPyBF4 give the
best results in terms of yield and reaction times. As can be
seen from Table 1, the ionic liquids can truly be compared
with classical molecular solvents, with the advantage of
rate acceleration and increase of yield. For example, using
the classical molecular solvents, such as acetonitrile, the
preparation of 2-phenylimidazo[1,2-a] pyridine (3a)
needs refluxing for 6 hours.22 But, the same reaction was
successful in the ionic liquid BPyBF4 at room temperature
in only 1 hour and gave a higher yield.
Key words: ionic liquid, 2-aminopyridine -tosyloxyketones, cy-
clocondensation
Room temperature ionic liquids (RTIL) are a new class of
solvents. These solvents possess a number of interesting
properties, especially their lack of vapour pressure, a
widely accessible temperature range with lack of flamma-
bility and ease of reuse. Recently, room temperature ionic
liquids are attracting increasing interest as environmental-
ly benign reaction media for synthetic organic chemistry.1
To date some of the more important reactions which have
been carried out and investigated in ionic liquids are, for
example, Friedel–Crafts reactions,2 alkylations,3 hydroge-
nations,4 Diels–Alder reactions,5 Wittig reactions,6 Heck
reactions,7 Michael additions,8 Suzuki reactions,9 epoxi-
dations,10 1,3-dipolar cycloaddition reactions,11 oxidation
of aromatic aldehydes,12 the Knoevengel, and Robinson
annulation reactions,13 etc.
NH2
O
Na2CO3
+
OTs
N
Ph
1a
2
N
Ph
N
Our recent interest has been in the area of clean synthesis
using -tosyloxyketones to replace lachrymatory and tox-
ic -haloketones for the synthesis of five-membered het-
erocycles.14 As part of a programme to investigate the
range of organic reactions possible in ionic liquids, we
were interested in the reaction of -tosyloxyketones with
2-aminopyridine to form imidazo[1,2-a]pyridine deriva-
tives in ionic liquids. Imidazo[1,2-a]pyridine derivatives
have been widely used as long-acting local anesthetic15
and antiulcer agents,16 for whitening fine fabrics,17 as an-
thelmintic or bacteriostatic agents,18 and as fluorescent
materials.19 They are also versatile intermediates for syn-
thetic transformations.20
3a
Scheme 1
Table 1 Cyclocondensation of -Tosyloxyacetophenone (1a) with
2-Aminopyridine (2) in Different Solvents to form 3a
Entrya
Solvent
Reaction
Temp (°C)
Reaction
Time (h)
Yield
(%)b
1
2
3
4
MeCN
80
25
25
25
6
1
3
3
70
81
72
75
BPyBF4
BMImBF4
BMImPF6
For this study, butylpyridinium tetrafluoroborate
(BPyBF4), 1-butyl-3-methylimidazolium tetrafluorobo-
rate (BMImBF4) and 1-butyl-3-methylimidazolium
a All reactions were run with -tosyloxyacetophenone (1a; 1 mmol),
2-aminopyridine (2; 1.2 mmol) and Na2CO3 (0.55 mmol) in 2 mL of
solvent.
b Isolated yield based on -tosyloxyacetophenone (1a).
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1505,1508,ftx,en;F01502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1506
Y.-Y. Xie et al.
PAPER
The scope of the cyclocondensation of various -tosyl- can be reused with no appreciable decrease in yield. The
oxyketones 1 with 2-aminopyridine (2) in BPyBF4 was in- results are summarized in Table 3.
vestigated. We found that the cyclocondensation of
-
Table 3 Results Obtained Using Recycled Ionic Liquid
tosyloxyketones 1 with 2-aminopyridine (2) occurred eas-
ily in BPyBF4 at room temperature in the presence of so-
dium carbonate to form the corresponding imidazo[1,2-
a]pyridine derivatives 3 (Scheme 2, Table 2).
Entry
Product
3a
Cycle
Yield (%)a
1
2
3
1
2
3
81
82
80
3a
3a
a Isolated yield based on -tosyloxyketones 1.
As part of a programme to investigate the scope of organic
reactions possible in ionic liquids, recently, we found that
-tosyloxylation of ketones can be performed by treat-
ment of ketones with [hydroxy(tosyloxy)iodo]benzene
(HTIB) in ionic liquids.23 Hence, we envisaged that imi-
dazo[1,2-a]pyridines 3 could be directly prepared by a
one-pot procedure through treatment of ketones with
HTIB and 2-aminopyridine (2) successively in BPyBF4.
Our experiments showed a one-pot procedure for the
preparation of imidazo[1,2-a]pyridine derivatives 3 by
cyclocondensation of ketones with [hydroxy(tosyloxy)io-
do]benzene and 2-aminopyridine (2) in ionic liquid
(BPyBF4) was successful (Scheme 3). The results are
summarized in Table 4.
Scheme 2
In fact, simple stirring of a mixture of -tosyloxyketones
1, 2-aminopyridine (2) and sodium carbonate in BPyBF4
at room temperature for about one hour gave, after extrac-
tion with diethyl ether, the desired imidazo[1,2-a]py-
ridines 3 in good yields. All reactions exhibited
pronounced rate accelerations and good yields were ob-
tained for the isolated products 3. The results are summa-
1
rized in Table 2. The products were characterized by H
NMR, IR and melting points which were consistent with
the literature data.
The ionic liquid can be typically recovered by extracting
out the product first and filtering the suspension to remove
residual sodium carbonate and precipitated sodium tosy-
late followed by vacuum drying. The recovered solvent
Scheme 3
Table 2 Cyclocondensation of -Tosyloxyketones 1 with 2-Aminopyridine (2) in BPyBF4
Product
3a
R1
R2
H
Yield (%)a
Mp (°C)b
130–132
158–160
200–202
210–212
140–141
133–134
153–154
92–94
Lit. mp (°C)
13524
Ph
81
90
79
77
72
90
72
76
3b
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
Ph
H
165–16625
205–20626
215–21627
144–14526
137–13826
158–16028
90–9126
3c
H
3d
H
3e
H
3f
H
3g
Me
H
3h
a Isolated yield based on -tosyloxyketones 1.
b Melting points are uncorrected.
Synthesis 2002, No. 11, 1505–1508 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclocondensation Reactions in Ionic Liquids
1507
Table 4 One-Pot Synthesis of Imidazo[1,2-a]pyridines 3 in BPyBF4
2-(4-Bromophenyl)imidazo[1,2-a]pyridine (3d)
IR: 1634 cm–1 (C=N).
Entry
R1
R2
H
H
H
Yield (%)a
1H NMR: = 6.78–6.81 (t, J = 6.7 Hz, 1 H), 7.17–7.21 (m, 1 H),
7.55–7.57 (m, 2 H), 7.61–7.64 (d, J = 9.1 Hz, 1 H), 7.82 (s, 1 H),
7.82–7.85 (m, 2 H), 8.10–8.12 (d, J = 6.8 Hz, 1 H).
1
2
3
Ph
81
85
74
4-FC6H4
4-ClC6H4
2-(4-Methylphenyl)imidazo[1,2-a]pyridine (3e)
IR: 1633 cm–1 (C=N).
a Isolated yield based on ketone.
1H NMR: = 2.39 (s, 3 H), 6.76–6.79 (t, J = 6.7 Hz, 1 H), 7.15–7.18
(t, J = 7.9 Hz, 1 H), 7.24–7.26 (d, J = 8.2 Hz, 2 H), 7.63–7.65 (d,
J = 9.0 Hz, 1 H), 7.83 (s, 1 H), 7.85–7.87 (d, J = 8.1 Hz, 2 H), 8.10–
8.12 (d, J = 6.7 Hz, 1 H).
In conclusion, room temperature ionic liquid BPyBF4 is
an attractive clean synthetic alternative to classical molec-
ular solvents for cyclocondensation of -tosyloxyketones
1 with 2-aminopyridine (2) and give significant rate accel-
erations and improved yields of products. Separation of
products from the ionic liquids is very straight forward, as
is recycling of the ionic liquid.
2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3f)
IR: 1634 cm–1 (C=N).
1H NMR: = 3.86 (s, 3 H), 6.74–6.78 (t, J = 6.8 Hz, 1 H), 6.97–6.99
(d, J = 6.8 Hz, 2 H), 7.13–7.17 (t, J = 7.9 Hz, 1 H), 7.60–7.62 (d,
J = 9.1 Hz, 1 H), 7.78 (s, 1 H), 7.89–7.90 (d, J = 6.8 Hz, 2 H), 8.10–
8.11 (d, J = 6.8 Hz, 1 H).
3-Methyl-2-phenylimidazo[1,2-a]pyridine (3g)
IR spectra were recorded as KBr pellets on VECTOR-22
IR Spectrophotometer. 1H NMR spectra were recorded on
Bruker 400 MHz spectrometer in CDCl3 using TMS as an
internal standard.
IR: 1634 cm–1 (C=N).
1H NMR: = 2.65 (s, 3 H), 6.84–6.88 (t, J = 6.8 Hz, 1 H), 7.16–7.20
(t, J = 7.9 Hz, 1 H), 7.34–7.37 (m, 1 H), 7.45–7.49 (m, 2 H), 6.64–
6.67 (d, J = 9.1 Hz, 1 H), 7.80–7.82 (m, 2 H), 7.90–7.92 (d, J = 6.8
Hz, 1 H).
2-Phenylimidazo[1,2a]pyridine (3a); Typical Procedure
-Tosyloxyacetophenone (1a; 0.29 g, 1 mmol), 2-aminopyridine (2;
0.11 g, 1.2 mmol), and Na2CO3 (0.06 g, 0.55 mmol) were added to
BPyBF4 (2 mL). The resulting mixture was stirred at r.t. for 1 h.
Subsequently, the reaction mixture was extracted with Et2O (6 10
mL). The remaining ionic liquid suspension was filtered, and reused
after drying in vacuum. The combined ethereal solution was evap-
orated under reduced pressure. The crude product was purified by
preparative TLC (EtOAc–cyclohexane, 1:2) to give 3a (0.156 g,
81%) as a white solid.
2-(2-Furyl)imidazo[1,2-a]pyridine (3h)
IR: 1636 cm–1 (C=N).
1H NMR: = 6.51–6.52 (m, 1 H), 6.78–6.81 (t, J = 6.8 Hz, 1 H),
6.91 (d, J = 3.2 Hz, 1 H), 7.17–7.21 (t, J = 7.8 Hz, 1 H), 7.47–7.48
(t, J = 0.8 Hz, 1 H), 7.60–7.63 (d, J = 9.1 Hz, 1 H), 7.80 (s, 1 H),
8.10–8.12 (d, J = 6.8 Hz, 1 H).
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Synthesis 2002, No. 11, 1505–1508 ISSN 0039-7881 © Thieme Stuttgart · New York