Modification of thionucleobases in ionic liquids

Article abstract of DOI:10.1155/2014/353797

A simple method was established for the preparation of thio-substituted thionucleobases using room temperature ionic liquids (RTILs) such as 1-butyl-3-methylimidazolium trifluoroacetate [BMIM]⁺[CF₃COO]^- and 1-methoxyethyl-3-methylimidazolium trifluoroacetate [MeOEtMIM]⁺[CF₃COO]^- as solvents and catalysts without any other catalyst. These reactions proceeded efficiently in RTILs with excellent yield of products. RTILs can be recycled and reused effectively without further purification.

Full text of DOI:10.1155/2014/353797

Hindawi Publishing Corporation
Journal of Chemistry
Volume 2014, Article ID 353797, 4 pages
http://dx.doi.org/10.1155/2014/353797
Research Article
Modification of Thionucleobases in Ionic Liquids
Xiaomei Hu,1 Bixian Zhang,2 Shijia Dong,1 and Yunfei Gao2
1 School of Life and Science, Northeast Agricultural University, Harbin 150030, China
2 Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
Correspondence should be addressed to Xiaomei Hu; huxiaomei1982@163.com
Received 15 August 2014; Accepted 22 September 2014; Published 21 October 2014
Academic Editor: Joaquin Campos
Copyright © 2014 Xiaomei Hu et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A simple method was established for the preparation of thio-substituted thionucleobases using room temperature ionic liquids
(RTILs) such as 1-butyl-3-methylimidazolium trifluoroacetate [BMIM]+[CF COO]− and 1-methoxyethyl-3-methylimidazolium
3
trifluoroacetate [MeOEtMIM]+[CF COO]− as solvents and catalysts without any other catalyst. ese reactions proceeded
3
efficiently in RTILs with excellent yield of products. RTILs can be recycled and reused effectively without further purification.
1. Introduction
[6–8]. As 6-mercaptopurine and 6-thioguanine have been
used as effective anticancer and anti-inflammatory drugs it
is worthwhile to explore modified thionucleobases. Various
RTILs have been prepared. A series of thio-substituted nucle-
obases were synthesized in RTILs and a possible mechanism
was proposed.
Nucleoside chemistry is an important research area in drug
development. Various kinds of chemical modified nucle-
obases, nucleosides, and oligonucleotides have biological
activities. 6-Mercaptopurine and 6-thioguanine have been
found in 1950s [1, 2]. Nowadays, they are commonly used as
clinical drugs for the treatment of leukaemia or inflamma-
tory bowel disease. Elgemeie synthesized a series of nucle-
obase analogues [3]. 2-ioalkylsubstituted purines and 6-
mercapto-9-substituted purines showed active antileukaemia
in mice [4]. Another significant work was reported by
Kumar. 6-Methylthioguanine has a certain function to trigger
cell death [5]. eir work indicates that thio-substituted
nucleobases have potential antitumors or anti-inflammatory
activities.
2. Experimental Section
Chemicals were purchased from Alading Company (China)
and Aldrich Company and were used as received. Mass
spectrometry (APCI-MS) was carried out on a Hewlett-
1
Packard 5989B quadrupole instrument. H NMR spectra
were recorded on a Bruker AC-250 instrument.
However, one of the big problems associated with the
nucleoside chemistry is the poor solubility of these nucle-
obase or nucleoside compounds in the commonly used
organic solvents. ere is an urgent need to develop alter-
native solvents and technologies. Ionic liquids provide an
opportunity to solve this problem. Room temperature ionic
liquids (RTILs) as “green solvents” have gained wide pop-
ularity in recent years for their increasing applications as
they possess a number of interesting properties such as a
widely accessible temperature range, low vapor pressure, and
lack of flammability and ease of reuse. erefore they are
considered to be environmentally friendly reaction mediums
2.1. e Synthesis of Room Temperature Ionic Liquids. 1-Meth-
ylimidazole (0.1 mol) was added dropwise to 1-chlorobutane
(0.2 mol). e mixture was stirred vigorously and refluxed
at 80∘C for 24 h. When the reaction was completed, the
excess 1-chlorobutane was decanted and the crude ionic
liquid was washed with chlorobutane (2 × 5 mL). e
trace of remaining 1-chlorobutane was removed with rotary
evaporation at 60∘C for 30 min. e crude product was
further purified by recrystallization (acetonitrile/ether) and
dried under vacuum to give [BMIM]+Cl−. A solution of
[BMIM]+Cl− (0.1 mol) in acetonitrile was added to a solution
of sodium trifluoroacetate (0.1 mol) in acetone. e reaction

2
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Table 1: Preparation of thio-substituted nucleobase in various ionic liquids.
Entry
1
2
3
4
5
6
7
Reactant 1
Reactant 2
Time
0.5 h
0.5 h
24 h
6 h
6 h
6 h
0.5 h
6 h
0.5 h
24 h
24 h
24 h
24 h
6 h
Yield (%)
94
Ionic liquid
[MeOEtMIM]+[CF3COO]−
[BMIM]+[CF3COO]−
[BMIM]+[CF3COO]−
[MeOEtMIM]+[CF3COO]−
[BMIM]+[CF3COO]−
DMSO
6-Mercaptopurine
6-Mercaptopurine
6-Mercaptopurine
6-Mercaptopurine
6-Mercaptopurine
6-Mercaptopurine
6-ioguanine
Benzyl bromide
Benzyl chloride
1-Bromopropane
1-Iodobutane
1-Iodobutane
1-Iodobutane
88a
72a
94
89
n
88
92
93
92
92
83
Benzyl bromide
1-Iodobutane
[MeOEtMIM]+[CF3COO]−
[MeOEtMIM]+[CF3COO]−
[BMIM]+[CF3COO]−
[MeOEtMIM]+[CF3COO]−
[PhOEtMIM]+[CF3CF2COO]−
[BMIM]+[CF3COO]−
DMSO
8
9
6-ioguanine
2-Mercaptopyrimidine
2-Mercaptopyrimidine
2-Mercaptopyrimidine
2-Mercaptopyrimidine
2-Mercaptopyrimidine
Benzyl bromide
1-Bromopropane
1-Bromopropane
1-Bromopropane
1-Bromopropane
1-Iodobutane
10
11
12
13
14
n
90
2-Mercaptopyrimidine
[BMIM]+[CF3COO]−
aReaction temperature was 60 C. n: no isolated yield of product.
∘
O
O
N
N
N
N
N
N
N
N
[BMIM]+
[BMMIM]+
[MeOEtMIM]+
[PhOEtMIM]+
Figure 1: Chemical structure of the cations of ILs.
was continued for 4 h. Afer that, the white solid NaCl
was filtered off and the solvent was removed by rotary
[CF CF COO]− (Figure 1) were investigated. ILs with
3
2
the anion of [CF COO]−, [CF CF COO]− have a good
3
3
2
evaporation. e resulting product ([BMIM]+[CF COO]−)
solubility for all of the tested thionucleobases and ILs with
3
was kept in a high vacuum to give a yield of 92%. 96% of
the anions of [BF ]− and [PF ]− have a very poor solubility.
4
6
[BMIM]+[Cl]−, 91% of [MeOEtMIM]+[CF COO]−, 90% of
e synthetic approach was straightforward. iopurines
or thiopyrimidines and haloalkanes were mixed in one of
the ILs. e mixture was stirred for an appropriate time
at 25∘C and the results were summarized in Table 1. As
expected, alkyl iodide was more reactive than alkyl bromide
and chloride due to the nucleophilic order of halide ions. All
reactions occurred in the ionic liquids at room temperature
without any other catalyst.
3
[PhOEtMIM]+[CF CF COO]−, 95% of [BMMIM]+Cl−, and
3
2
91% of [BMMIM]+[CF COO]− were prepared by a similar
3
method [8].
2.2. Nucleobase Reactions. A thiopurine (1 mmol) and a
halide (1 mmol) were mixed in one of the ionic liquids.
e reaction mixture was stirred for an appropriate time at
25∘C. When TLC analysis had indicated that the reaction
was completed, water (5 mL) was added to the mixture.
e resulting product was extracted with ethyl acetate (3
× 10 mL) and the extraction was washed with water (2 ×
10 mL). Ethyl acetate was removed by rotary evaporation. e
product was further dried overnight under vacuum. Water
was removed under high vacuum rotary evaporation to afford
the recovered ionic liquid.
As shown in Table 1, good yields of the products
were obtained when the reactions were carried out in
[PhOPMIM]+[CF CF COO]−, [MeOEtMIM]+[CF COO]−,
3
2
3
and [BMIM]+[CF COO]−. In contrast, very low yield of
3
product was obtained in DMSO under the same reaction
conditions. Surprisingly, when 2-mercaptopyrimidine was
reacted with bromopropane in ILs, the resulting product
of 2-propyl-mercaptopyrimidine was obtained. When they
reacted in DMSO in the absence of triethylamine, no
expected product was obtained, but a product of Di-2-
pyrimidinyl disulfide was observed.
3. Results and Discussion
In general, the thio-substituted nucleobase reaction of 6-mer-
captopurine with benzyl bromide should be carried out with
the use of triethylamine. Interestingly, it was found that ionic
liquids had a catalytic activity to promote these reactions and
satisfactory yields of products were obtained. en a series of ILs
such as [BMIM]+[CF COO]−, [BMIM]+[BF ]−, [BMIM]+
Following the experiments above, it was supposed
that the catalytic activities of ILs are related to the C(2)
hydrogen on the imidazole ring. e thio-substituted reac-
tion of 6-mercaptopurine with benzyl chloride was per-
formed for 30 min and reaction of 6-mercaptopurine with 1-
bromopropane was performed for 24 h at 60∘C. As shown in
Figure 2, with the same anion, a little higher yield of product
3
4
[PF ]−, and [MeOEtMIM]+[CF COO]−, [PhOEtMIM]+
6
3

Journal of Chemistry
3
100
80
60
40
20
0
(a)
(b)
[BMIM]+[Cl]−
[BMMIM]+[CF3COO]−
DMSO
[BMMIM]+[Cl]−
[BMIM]+[CF3COO]−
Figure 2: Reactions of 6-mercaptopurine with benzyl chloride (a) or 1-bromopropane (b).
10
9
8
7
6
5
4
3
2
1
(ppm)
(a)
10
9
8
7
6
5
4
3
2
1
(ppm)
(b)
Figure 3: 1H NMR of [BMIM]+[Cl]− (a) and [BMIM]+[Cl]− with 6-mercaptopurine (b).
was observed with ILs in the order of [BMMIM]+ > [BMIM]+
for both of the reactions. It indicated that the replacing of
hydrogen using methyl decreases the activity of the hydrogen
bond, which benefits the substituted reactions.
9.510. When 6-mercaptopurine was added to [BMIM]+[Cl]−,
this chemical shif was moved to a lower position of 9.378.
erefore, a supposed activity of IL was shown in Figure 4.
When the hydrogen of C(2) of imidazolium ring was replaced
by methyl, it lowered the hydrogen bond of cation and
anion of ILs; the anion of ILs functions with the hydrogen
In addition, from 1H NMR (Figure 3), the chemical shifs
of C(2) hydrogen in the imidazole ring of [BMIM]+[Cl]− were

4
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Acknowledgments
N
N
is work was financially supported by Heilongjiang Human
Resources and Social Security for the Scientific Research
Foundation of Returned Overseas Chinese Scholars,
Heilongjiang Postdoctoral Foundation (LBH-Q13019), and
Northeast Agricultural University Doctoral Foundation
(2010RCB58).
X−
H
H
S
N
N
N
N
References
H
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Figure 4: A supposed activity of the ionic liquid.
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Fresh
Cycle 1
Recycled ionic liquid
Cycle 2
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Figure 5: Reaction of 6-mercaptopurine with 1-iodobutane in the
recycled [MeOEtMIM]+[CF COO]−.
3
of thionucleobase was stronger, which accelerate the thio-
substituted reactions.
In order to determine whether recovered ionic liquids
would affect the reaction rates or the yields of the products,
reaction of 6-mercaptopurine with 1-iodobutane was carried
out in the recycled [MeOEtMIM]+[CF COO]− at room
3
temperature for 6 h. e reactions proceeded efficiently in the
recovered ionic liquids as shown in Figure 5. RTILs could be
reused without obvious decrease in both the product yields.
4. Conclusions
e thio-substituted reactions could be carried out effec-
tively and efficiently in RTILs. e ionic liquids such as
[BMIM]+[CF COO]− and [MeOEtMIM]+[CF COO]− are
3
3
excellent reaction solvents as they provide good solubility and
also generate excellent catalytic ability. ionucleobases with
different substituents are produced with excellent yields. e
experimental approach is simple. Ionic liquids can be reused
without significant decrease of yields. e approach has a
great potential in their application in nucleoside chemistry.
Conflict of Interests
e authors declare that there is no conflict of interests
regarding the publication of this paper.
Authors’ Contribution
Xiaomei Hu and Bixian Zhang contributed equally to this
work. Both of them are first authors.

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