Organic reactions in ionic liquids: Ionic liquid-accelerated one-pot synthesis of 2-arylimidazo[1,2-a]pyrimidines

Article abstract of DOI:10.1081/SCC-200063911

The room-temperature ionic liquid n-butylpyridinium tetrafluoroborate (BPyBF₄) is used as a recyclable alternative to classical molecular solvents in the one-pot synthesis of 2-arylimidazo[1,2-a]pyrimidines by reaction with ketones, [hydroxy(tosyloxy)iodo]benzene, and 2-aminopyrimidine. Significant rate enhancements and improved yields have been observed. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200063911

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Organic Reactions in
Ionic Liquids: Ionic
Liquid‐Accelerated
One‐Pot Synthesis of
2‐Arylimidazo[1,2‐a]pyrimidines
Yuan‐Yuan Xie a
a College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou, China
Published online: 15 Aug 2006.
To cite this article: Yuan‐Yuan Xie (2005) Organic Reactions in Ionic Liquids: Ionic
Liquid‐Accelerated One‐Pot Synthesis of 2‐Arylimidazo[1,2‐a]pyrimidines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:13, 1741-1746, DOI: 10.1081/SCC-200063911
To link to this article: http://dx.doi.org/10.1081/SCC-200063911
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Synthetic Communicationsw, 35: 1741–1746, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063911
Organic Reactions in Ionic Liquids: Ionic
Liquid-Accelerated One-Pot Synthesis of
2-Arylimidazo[1,2-a]pyrimidines
Yuan-Yuan Xie
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, China
Abstract: The room-temperature ionic liquid n-butylpyridinium tetrafluoroborate
(BPyBF4) is used as a recyclable alternative to classical molecular solvents in the
one-pot synthesis of 2-arylimidazo[1,2-a]pyrimidines by reaction with ketones, [hydro-
xy(tosyloxy)iodo]benzene, and 2-aminopyrimidine. Significant rate enhancements and
improved yields have been observed.
Keywords: 2-Aminopyrimidine, 2-arylimidazo[1,2-a]pyrimidine, ionic liquid, one-pot
synthesis
Imidazo[1,2-a]pyrimidine derivatives constitute an important class of organic
compounds that have been widely used as azo dyes,[1] fabric whiteners,[2] and
antimicrobial agents.[3] In addition they possess an antagonistic activity
against that of purines.[4] Despite their wide applicability, feasible routes for
their synthesis are limited. Typically, they are synthesized by the cyclocon-
densation of 2-aminopyrimidine with the suitable a-bromoacetophenones in
solvents such as DME,[5] ethanol,[6] acetone,[7] and DMF.[8] Unfortunately,
a long reaction time is necessary and the yield is poor. In addition, a-bromo-
acetophenones are lachrymatory, toxic, and not readily available. Therefore,
the development of a mild, efficient, environmentally friendly method to
Received in Japan February 14, 2005
Address correspondence to Yuan-Yuan Xie, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, China. E-mail: xyycz@zjut.
edu.cn
1741

1742
Y.-Y. Xie
Scheme 1.
prepare 2-arylimidazo[1,2-a]pyrimidines is still presently significant in
organic synthesis.
In recent years, the use of room-temperature ionic liquids has attracted
increasing interest as a recyclable alternative to classical molecular solvents
in synthetic organic chemistry. Many reports have been published showing
improved reaction yields and rates.[9] Our recent interest has been in the deve-
lopment of new synthetic methods using ionic liquids as reaction media and
promoters.[10] As part of a program to investigate the range of possible
organic reactions in ionic liquids, we studied the one-pot reaction of
ketones, [hydroxy(tosyloxy)iodo]benzene (HTIB), and 2-aminopyrimidine
to form imidazo[1,2-a]pyrimidine derivatives.
In this study, n-butylpyridinium tetrafluoroborate (BPyBF4), 1-butyl-3-
methyl-imidazolium tetrafluoroborate (BMImBF4), and 1 -butyl-3-methylimi-
dazolium hexafluorophosphate (BMImPF6) were synthesized according to the
procedures reported in the literature.[11]
At first, we examined the efficacy of different ionic liquids in the cyclo-
condensation of a-tosyloxyacetophenone (1) with 2-aminopyrimidine (2)
(Scheme 1). The results summarized in Table l showed that BPyBF4 gave
the best results in terms of yield and reaction time. As shown in Table 1, the
ionic liquids, compared with classical molecular solvents, had the advantage
of rate acceleration and increased yields. For example, the preparation of
2-phenylimidazo[1,2-a]pyrimidine (3a) needed refluxing for 6 h in the
classical molecular solvents, such as ethanol; however, in ionic liquid
Table 1. Effect of solvent on the cyclocondensation of a-tosyloxyacetophenone with
2-aminopyrimidine
Reaction
temperature (8C)
Reaction
time (h)
Yieldb
(%)
Entrya
Solvent
1
2
3
4
Ethanol
BPyBF4
80
25
25
25
6
1
1
1
70
82
72
71
BMImBF4
BMImPF6
aAll reactions were run with a-tosyloxyacetophenone, 1 mmol; 2-aminopyrimidine,
1.2 mmol; and sodium carbonate, 0.55 mmol in 2 mL of solvent.
bIsolated yield based on a-tosyloxyacetophenone.

Organic Reactions in Ionic Liquids
1743
Scheme 2.
(BPyBF4), the reaction took place at room temperature for 1 h and gave a higher
yield.
Previously, we had found that a-tosyloxylation of ketones can be
perfomed by treatment of ketones with HTIB in ionic liquids.[10b] As a conse-
quence of this finding, we reasoned that imidazo[1,2-a]pyrimidines could be
directly prepared by a one-pot procedure through the treatment of ketones
with HTIB and 2-aminopyrimidine successively in BPyBF4. Our experiments
showed this one-pot procedure for the preparation of imidazo[1,2-a]pyrimi-
dine derivatives was indeed successful (Scheme 2). The results are summ-
arized in Table 2.
In fact, all reactions exhibited pronounced rate acceleration, and good
yields were also obtained for isolated products (3). All the products were
characterized by 1H-NMR, IR, and mp, which were consistent with literature
data.
The ionic liquid could be typically recovered by first extracting out the
product with an organic solvent; followed by filtering the ionic liquid,
which contained residual insoluble sodium carbonate and sodium tosylate;
then drying in vacuum. The recovered solvent could be reused several times
Table 2. One-pot synthesis of imidazo[1,2-a]pyrimidines (3) through the cyclocon-
densation of ketones with HTIB and 2-aminopyrimidine in BPyBF4
Product
R1
R2
Yielda (%)
Mpb (8C)
Lit. mp (8C)
3a
3b
3c
3d
3e
3f
Ph
H
H
80
85
83
81
75
72
76
73
190–192
236–238
266–268
218–221
236–238
188–190
206–208
208–210
195[5]
p-FC6H4
p-ClC6H4
p-BrC6H4
p-CH3C6H4
p-CH3OC6H4
Ph
239[5]
H
270[5]
H
224[5]
H
242[6]
H
190[4]
3g
3h
Me
H
211[12]
212–214[13]
aIsolated yield based on ketone.
bMelting points were uncorrected.

1744
Y.-Y. Xie
Table 3. Results obtained using recycled ionic liquid
Yielda
Entry
Product
Cycle
(%)
1
2
3
3a
3a
3a
1
2
3
80
82
80
aIsolated yield based on acetophenone.
without appreciable decrease in yield. The representative results are summar-
ized in Table 3.
In conclusion, we have provided a convenient synthetic method for
imidazo[1,2-a]pyrimidine derivatives by the cyclocondensation of ketones
with HTIB and 2-aminopyrimidine in room-temperature ionic liquid, BPyBF4,
by a one-pot procedure. In comparison with reported methods in the litera-
ture, the present method has some advantages, such as more environmental
friendliness, enhanced reaction rates, mild reaction conditions, simple manipu-
lation, ready isolation of the product, and higher yields. Moreover, the ionic
liquid can be recycled without decrease of yield.
EXPERIMENTAL
IR spectra were recorded as KBr pellets on a Vector-22 spectrophotometer.
1H-NMR spectra were recorded on Bruker 400-MHz spectrometer using
CDC13 as the solvent with TMS as an internal standard.
Procedure for synthesis of 2-phenylimidazo[1,2-a]pyrimidine (3a):
a-Tosyloxyacetophenone(0.29 g,l mmol),2-aminopyrimidine(0.11g,l.2 mmol)
and sodium carbonate (0.06g, 0.55mmol) were added to BPyBF4 (2 mL). The
resulting mixture was stirred at room temperature for 1 h. Subsequently, the
reaction media was extracted with ethyl acetate (6 ꢀ 10mL). The remaining
ionic liquid solution was filtered and reused. The combined ethyl acetate
solution was evaporated under reduced pressure. The crude product was
purified by preparative TLC (ethyl acetate) to give 3a (0.16 g, 82% yield) as a
white solid.
Typical one-pot procedure for synthesis of 2-phenylimidazo[1,2-a]pyri-
midine (3a): Acetophenone (0. 12 g, 1 mmol) and HTIB (0.392 g, 1 mmol)
were added successively to BPyBF4 (2 mL) with efficient stirring. The
resulting mixture was stirred for 1 h at 908C and then cooled to room tempera-
ture. After that, 2-aminopyrimidine (0.11 g, 1.2 mmol) and sodium carbonate
(0.06 g, 0.55 mmol) were added, and the mixture was stirred at room tempera-
ture for l h. Subsequently, the reaction media was extracted with ethyl acetate

Organic Reactions in Ionic Liquids
1745
(6 ꢀ 10 mL). The combined ethyl acetate solution was evaporated under
reduced pressure. The crude product was purified by preparative TLC (ethyl
acetate) to give 3a (0.155 g, 80% yield) as a white solid.
SPECTROSCOPIC DATA
2-Phenylimidazo[1,2-a]pyrimidine (3a): This compound was obtained as
1
a white solid. IR (cm21) 1634 (C55N); H-NMR, ppm: d 6.85–6.88 (m, 1H),
7.34–7.37 (t, J ¼ 7.4 Hz, 1H), 7.41–7.45 (t, J ¼ 7.6 Hz, 2H), 7.87 (s, 1H),
8.00–8.02 (d, J ¼ 7.2 Hz, 2H), 8.49–8.52 (m, 2H).
2-(4-Fluorophenyl)imidazo[1,2-a]pyrimidine (3b): This compound was
1
obtained as a white solid. IR (cm21) 1615 (C55N); H-NMR, ppm: d 6.86–
6.89 (m, 1H), 7.12–7.16 (t, J ¼ 8.7 Hz, 2H), 7.78 (s,1H), 7.99–8.03
(m, 2H), 8.42–8.44 (m, 1H), 8.53–8.54 (m, 1H).
2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine (3c): This compound was
1
obtained as a white solid. IR (cm21) 1614 (C55N); H-NMR, ppm: d 6.93–
6.96 (m, 1H), 7.42–7.44 (d, J ¼ 8.5 Hz, 2H), 7.85 (s, 1H), 7.94–7.96
(d, J ¼ 8.5 Hz, 2H), 8.47–8.50 (m, 1H), 8.59–8.60 (m, 1H).
2-(4-Bromophenyl)imidazo[1,2-a]pyrimidine (3d): This compound was
1
obtained as a white solid. IR (cm21) 1613 (C55N); H-NMR, ppm: d 6.87–
6.90 (m, 1H), 7.57–7.59 (d, J ¼ 8.4 Hz, 2H), 7.82 (s, 1H), 7.90–7.92
(d, J ¼ 8.5 Hz, 2H), 8.42–8.44 (m, 1H), 8.55–8.56 (m, 1H).
2-(4-Methylphenyl)imidazo[1,2-a]pyrimidine (3e): This compound was
1
obtained as a white solid. IR (cm21) 1616 (C55N); H-NMR, ppm: d 2.40
(s, 3H), 6.83–6.86 (m, 1H), 7.25–7.27 (d, J ¼ 7.7 Hz, 2H), 7.79 (s, 1H),
7.91–7.93 (d, J ¼ 8.0 Hz, 2H), 8.41–8.43 (m, 1H), 8.52–8.53 (m, 1H).
2-(4-Methoxyphenyl)imidazo[1,2-a]pyrimidine (3f): This compound was
1
obtained as a white solid. IR (cm21) 1618 (C55N); H-NMR, ppm: d 3.86
(s, 3H), 6.82–6.85 (m, 1H), 6.97–7.00 (m, 2H), 7.74(s, 1H), 7.95–7.99
(m, 2H), 8.39–8.42 (m, 1H), 8.50–8.51 (m, 1H).
2-Pheny1-3-Methylimidazo[1,2-a]pyrimidine (3g): This compound was
1
obtained as a yellow solid. IR (cm21) 1610 (C55N); H-NMR, ppm: d 2.64
(s, 3H), 7.01–7.03 (t, J ¼ 5.0 Hz, 1H), 7.41–7.43 (m, 1H), 7.48–7.52 (t,
J ¼ 7.4 Hz, 2H), 7.87–7.88 (d, J ¼ 7.2 Hz, 2H), 8.35–8.36 (d, J ¼ 6.8 Hz,
1H), 8.58–8.60 (d, J ¼ 2.8 Hz, 1H).
2-(2-Furanyl)imidazo[1,2-a]pyrimidine (3h): This compound was obtained
1
as a yellow solid. IR (cm21) 1632 (C55N); H-NMR, ppm: d 6.35–6.63

1746
Y.-Y. Xie
(m, 1H), 6.92–6.95 (m, 1H), 7.06–7.09 (m, 1H), 7.78 (s, 1H), 8.14–8.15
(m, 1H), 8.54–8.56 (m, 1H), 8.95–8.99 (m, 1H).
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