Enhanced solubility and selective benzoylation of nucleosides in novel ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2006.11.155

Solubility and benzoylation study of both ribo- and deoxyribonucleosides is reported in a new ionic liquid MoeMIM·TFA; high selectivity for O-benzoylation is achieved.

Full text of DOI:10.1016/j.tetlet.2006.11.155

Tetrahedron Letters 48 (2007) 809–812
Enhanced solubility and selective benzoylation
of nucleosides in novel ionic liquid
Vineet Kumar,a,b Virinder S. Parmarb,* and Sanjay V. Malhotraa,*
aDepartment of Chemistry and Environmental Science, New Jersey Institute of Technology,
University Heights, Newark, NJ 07102, USA
bBioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
Received 8 November 2006; revised 21 November 2006; accepted 27 November 2006
Available online 19 December 2006
Abstract—Solubility and benzoylation study of both ribo- and deoxyribonucleosides is reported in a new ionic liquid Moe-
MIMÆTFA; high selectivity for O-benzoylation is achieved.
ꢀ 2006 Published by Elsevier Ltd.
Chemical synthesis of therapeutic oligonucleotides has
undergone a renaissance during the last decade due to
the emergence of antisense oligonucleotides and siRNA
as potential and selective inhibitors of gene expression.1
Furthermore, the discovery of AZT, ddC, d4T, etc. as
anti-HIV agents,2 has thrown new challenges before
the organic chemists to develop rapid and economical
process for the synthesis of these molecules. In fact, it
may now be possible to synthesize an oligomer, by solid
phase, in less time than it takes to protect the nucleo-
sides used in the synthesis. Thus, the methods for
suitable and selective protection/deprotection for the
synthesis of nucleoside monomers have become equally
important.
hazardous properties and other environment issues asso-
ciated with them. Hence, there is a great need for the
development of new methodologies for manipulation
of different functionalities in nucleosides using environ-
mentally benign media which could replace the conven-
tional solvents and provide sufficient solubility to
nucleosides, specially the ribonucleosides.
In recent years, ionic liquids (ILs) have attracted atten-
tion as green alternative to organic solvents and high-
tech reaction media of the future.13 This is owing to
their unique properties such as negligible vapour
pressure, high thermal stability, unprecedented ability
to dissolve a broad range of compounds of organic and
inorganic nature and their recyclability. One key reason
for considering ILs as reaction media in the nucleoside
chemistry is the potential to tune their physical property
by changing their structure and thereby, design a solvent
which could provide high solubility of nucleosides and,
hopefully also desirable selectivity. ILs with ether side
chain are known to dissolve glycolipids.14 Similarly, a
solubility study on deoxyribonucleosides found that 1-
methoxyethyl-3-methylimidazolium methanesulfonate
(MoeMIMÆMs) provide good affinity to dissolve deoxy-
nucleosides but gave no selectivity for their acylation
reactions and per-acyl derivative was the final product.15
Our initial study of benzoylation in ionic liquids using
benzoyl cyanide as benzoylating agent, gave high selec-
tivity of sugar hydroxyl groups over amine group of
the base of nucleosides.10 But limitation of this process
was the evolution of HCN as by product which is highly
toxic.
One of the most preferred and frequently used approach
for their protection is benzoylation. This is due to its sta-
bility towards many commonly encountered reaction
conditions, easy deprotection in basic medium3 and less
pronounced attitude to vicinal migration.4 The methods
reported for nucleoside benzoylation using benzoyl
chloride,5 benzoyltetrazole,6 benzoyltriazole7 and
benzoyl cyanide8–10 showed lack of selectivity. Further-
more, most of these studies are limited to deoxyribo-
series11,12 leaving ribonucleosides quite unexplored.
One of the major reasons for this is the poor solubility
of these compounds, specially ribonucleosides in com-
mon organic solvents. Most commonly used solvents
in nucleoside chemistry such as pyridine and DMF have
*
Corresponding authors. Fax: +1 973 596 3569 (S.V.M.); e-mail:
malhotra@njit.edu
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.155

810
V. Kumar et al. / Tetrahedron Letters 48 (2007) 809–812
We are glad to report that our efforts of finding suitable
ILs for nucleoside chemistry have led to synthesis of a
new ionic liquid 1-methoxyethyl-3-methylimidazolium
trifluoroacetate (MoeMIMÆTFA) (Fig. 1), which for
the first time provides high solubility and selectivity in the
benzoylation of both deoxyribo- and ribonucleosides.
500
450
400
350
300
250
200
150
100
50
MoeMIM.CF3COO
BMIM.CF3COO
EtPy.CF3COO
MoeMIM.Ms
Pyridine
DMF
The solubility of thymidine was first studied in ionic
liquids having 1-methoxyethyl-3-methylimidazolium as
cation with different anions namely PF6, BF4, Tf2N,
CF3COO. Interestingly hydrophobic ionic liquids
MoeMIMÆPF6 and MoeMIMÆTf2N and also hydrophilic
ionic liquid MoeMIMÆBF4 showed poor solubility for
thymidine.16 On the other hand, the new ionic liquid
MoeMIMÆTFA showed good solubility for thymidine
which is comparable with MoeMIMÆMs. The solubility
of thymidine in 1-butyl-3-methyimidazolium trifluoro-
acetate (BMIMÆTFA) and N-ethyl pyridinium trifluoro-
acetate (EtPyÆTFA) was also found to be better than
several other solvents tested by us and others.15 The
solubility analysis of thymidine in different ILs is shown
in Figure 2. As it show, anion of ionic liquid has signif-
icant influence on the IL properties.17
0
A
C
G
Nucleosides
Figure 3. Solubility comparison of ribonucleosides in ILs and organic
solvents.
literature.15 However, the change of cation had no sig-
nificant influence on the solubility.
With high solubility of nucleosides achieved in these ILs,
the next step was to find their utility in benzoyl protec-
tion of nucleosides. As a representative example,
benzoylation reactions on 20-dA was carried out using
benzoic anhydride and DMAP (as catalyst) at 50 ꢁC in
three ILs (MoeMIMÆMs, MoeMIMÆTFA and BMIMÆ
TFA) in which high solubility was obtained (Scheme 1).
Initially the reactions were carried out using 1 equiv of
benzoic anhydride but the conversion was only around
30% to give a mixture of 50-O-benzoyl, 30-O-benzoyl
and 50,30-di-O-benzoyl derivatives. Further addition of
3 equiv of benzoic anhydride was required for complete
benzoylation, which gave 50,30-di-O-benzoyl-20-deoxy-
adenosine as single product. The reactions were contin-
ued until all the starting material was consumed. We
found that with 4 equiv of benzoic anhydride, the reac-
tion proceed rapidly in all three ILs. Most importantly
the selectivity is very high for O-benzoylation in these
cases. Due to poor solubility of 20-dA in Moe-
MIMÆTf2N, MoeMIMÆPF6 and MoeMIMÆBF4 the reac-
tion took long time (more than 24 h) and also no
selectivity was observed. Interestingly however, using
EtPyÆTFA, gave highest solubility for both ribo- and
deoxyribo- nucleosides, but the benzoylation was very
slow and reactions did not complete even after three
days. The new ionic liquid MoeMIMÆTFA turned out
to be the best solvent for this system, as it took least time
to get the maximum selectivity (Scheme 1). When the
same reactions were carried out at room temperature,
the reaction profile was same but the conversion was
very slow and the reactions were not complete even after
24 h. Similar reactions were also carried out using vinyl
benzoate as benzoylating agent in different ILs, but no
selectivity was observed and the reaction ends up in a
complex mixture of compounds.
Next we studied the solubility of three ribonucleosides
viz. adenosine, cytosine and guanosine in ILs which
were found to be best in case of thymidine. The solubil-
ity in ILs, MoeMIMÆTFA, MoeMIMÆMs, BMIMÆTFA,
EtPyÆTFA was compared with conventionally used sol-
vents pyridine and DMF (Fig. 3). MoeMIMÆMs and Et-
PyÆTFA were found to be the best solvents followed by
MoeMIMÆTFA and BMIMÆTFA, respectively. In gen-
eral, the ILs tested in this study were found to be far bet-
ter solvents as compared to pyridine and DMF. The
enhanced solubility of ribonucleosides in these ILs
may be because these oxygenated anions may form
hydrogen bonding with the nucleosides which can
increase their solubility, as also suggested earlier in the
CF3COO
+
N
N
O
Figure 1. 1-Methoxyethyl-3-methylimidazolium trifluoroacetate (Moe-
MIMÆTFA).
EtP
y.T
FA
BM
IM.
IM.
TFA
Mo
eM
TFA
Mo
eM
IL
IM.M
s
Moe
MIM
.Tf
2N
Mo
Mo
eMIM.PF6
eM
IM.B
F4
Inspired by these results we used MoeMIMÆTFA to
study benzoylation of other nucleosides (both ribo and
deoxyribo-) under the same reaction conditions (Scheme
2).
0
100
200
300
400
500
Solubility (mg/ml)
Figure 2. Solubility analysis of thymidine in different ionic liquids.

V. Kumar et al. / Tetrahedron Letters 48 (2007) 809–812
811
NH2
NH2
N
N
N
N
N
N
Benzoic anhydride (4eq.)
DMAP, ILs, 50 ºC
O
N
BzO
O
N
HO
BzO
HO
3',5'-dibenzoyl-2'-deoxyadenosine
2'-deoxyadenosine
Entry
Ionic liquids
Time (h)
% Yield
1
2
3
MoeMIM.Ms
MoeMIM.TFA
BMIM.TFA
8
6
10
86
90
84
Scheme 1. Benzoylation of 20-dA in different ILs using benzoic anhydride.
5'
BzO
MoeMIM.TFA
B
O
B
O
Benzoic anhydride
DMAP, 50 ºC
HO
1'
4'
BzO
R'
HO
1a - 1d
R
2a - 2e
2a, B = thymin-1-yl, R = H
2b, B = thymin-1-yl, R = OBz
2c, B = adenin-9-yl, R = H
2d, B = adenin-9-yl, R = OBz
2e, B = cytosin-1-yl, R = OBz
2f, B = guanin-9-yl, R = H
2g, B = guanin-9-yl, R = OBz
1a, B = thymin-1-yl, R = H
1b, B = thymin-1-yl, R = OH
1c, B = adenin-9-yl, R = H
1d, B = adenin-9-yl, R = OH
1e, B = cytosin-1-yl, R = OH
1f, B = guanin-9-yl, R = H
1g, B = guanin-9-yl, R = OH
Starting
compd.
Bz2O
(equiv) time (h)
Reaction
Product Yield%
1a
1b
1c
1d
1e
1f
3
4
4
5
5
4
5
2.0
2.0
6.0
2.5
6.0
6.0
4.0
2a
2b
2b
2c
2d
2f
93
90
90
92
68
80
70
1g
2e
Scheme 2. Benzoylation of nucleosides in MoeMIMÆTFA using benzoic anhydride.
In all cases the selectivity is high and O-benzoylated
derivatives were formed in good yields. This could be
due to high ionic character of the ILs polarizing the
–O–H bond, thereby making the hydroxyl moiety more
nucleophilic then the –NH2 group of nucleosides. This
results in the selective O-benzoylation in all the cases.
5–8% loss of IL in recovery. The results of recyclability
studies with MoeMIMÆTFA are given in Table 1.
In summary we have synthesized a new ionic liquid
MoeMIMÆTFA which provides high solubility for
nucleosides. Also, it is an efficient reaction medium for
a selective benzoylation of nucleosides giving high yields
under ambient conditions. Also, for the first time high
solubility and selective derivatization of ribonucleoside
has been achieved with MoeMIMÆTFA, which otherwise
is a tedious task in the conventional organic solvents.
Further we tested the recyclability of ionic liquid Moe-
MIMÆTFA for benzoylation of adenosine.18 There was
no considerable drop in the selectivity and yield of
O-benzoylated derivative. However, we do observe about
Ionic liquids MoeMIMÆBF4,19 MoeMIMÆTf2N,19 Moe-
MIMÆPF6,19 MoeMIMÆMs,15 BMIMÆTFA,20 EtPyÆ
TFA21 were prepared by following the literature
procedure.
Table 1. Recyclability studies of MoeMIMÆTFAa
No. of cycles
Time taken (h)
Bz2O (equiv)
% Yield
0
1
2
2.5
3.0
3.0
5
5
5
92
90
89
Synthesis of MoeMIMÆTFA: To MoeMIMÆCl19 (20 g,
0.113 mol) taken in acetone (150 ml), CF3CO2Na
(24.63 g, 0.181 mol) was added. The mixture was stirred
a Recovered from benzoylation of adenosine.

812
V. Kumar et al. / Tetrahedron Letters 48 (2007) 809–812
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at room temperature for 24 h, the resulting precipitate
was filtered and washed with acetone (2 · 50 ml). The
filtrate was concentrated under vacuum and purified
by chromatography over silica gel using CH2Cl2 as
solvent to get the desired IL (25 g, 87%). 1H NMR
(300 MHz, acetone-d6); d = 3.30 (3H, s), 3.79 (2H, t,
J = 5.0 Hz), 4.03 (3H, s), 4.54 (2H, t, J = 4.9 Hz),
7.77–7.79 (2H, m), 9.46 (1H, s). 13C NMR (75 MHz,
acetone-d6); 36.39, 50.01, 58.73, 70.95, 118.26 (q,
J = 295.8 Hz), 123.82, 124.45, 138.53, 161.55 (q,
J = 33.0 Hz). MS (espꢀ): m/z 112.8 (100%, TFA),
(esp+) m/z 141 (100%, MoeMIM).
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General procedure for benzoylation: In a typical experi-
ment, the nucleoside (1 mmol) was taken in the ionic
liquid (1 ml), DMAP (20 mg) and benzoic anhydride
(amount for different nucleosides mentioned in Scheme
2) were added. The reaction mixture was stirred at
50 ꢁC till consumption of starting compound (TLC,
MeOH/CHCl3). Then water (10 ml) was added to the
reaction mixture and the benzoylated derivative was
precipitated out and filtered. The filtrate was proceeded
to recover IL and benzoylated derivative was further
washed with hot water to remove benzoic acid (which
is the byproduct here) and further purified by silica gel
column chromatography using MeOH/CHCl3 as solvent
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was added and benzoylated derivative was filtered off. The
filtrate was washed with diethyl ether (3 · 15 ml) and
concentrated under vacuum to get the ionic liquid back.
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Acknowledgement
This work was supported by a US Department of
Energy Laboratory Directed Research and Develop-
ment program at Brookhaven National Laboratory.
Authors would like to thank EMD Chemicals Inc. for
the generous gift of chemicals for chromatography.
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