Mild, efficient, selective and "green" benzoylation of nucleosides using benzoyl cyanide in ionic liquid

Article abstract of DOI:10.1081/NCN-200060065

Use of benzoyl cyanide (BzCN) for benzoylation of nucleosides has been studied, both in pyridine and in ionic liquid. BzCN in 1-methoxyethyl-3- methylimidazolium methanesulfonate as ionic liquid has been found to be a "green" alternative compared to the pyridine-BzCN system. An efficient and selective benzoylation of nucleosides of both, the 2′-deoxy- and the ribo-series at ambient temperature was accomplished. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200060065

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MILD, EFFICIENT, SELECTIVE AND “GREEN”
BENZOYLATION OF NUCLEOSIDES USING BENZOYL
CYANIDE IN IONIC LIQUID
Ashok K. Prasad a , Vineet Kumar a , Jyotirmoy Maity a , Yogesh S. Sanghvi b , Vasulinga T.
Ravikumar b & Virinder S. Parmar a
a Bioorganic Laboratory, Department of Chemistry , University of Delhi , Delhi, India
b Isis Pharmaceuticals Inc. , Carlsbad, California, USA
Published online: 15 Nov 2011.
To cite this article: Ashok K. Prasad , Vineet Kumar , Jyotirmoy Maity , Yogesh S. Sanghvi , Vasulinga T. Ravikumar & Virinder
S. Parmar (2005) MILD, EFFICIENT, SELECTIVE AND “GREEN” BENZOYLATION OF NUCLEOSIDES USING BENZOYL CYANIDE IN IONIC
LIQUID, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 747-751, DOI: 10.1081/NCN-200060065
To link to this article: http://dx.doi.org/10.1081/NCN-200060065
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):747–751, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060065
MILD, EFFICIENT, SELECTIVE AND ‘‘GREEN’’ BENZOYLATION OF
NUCLEOSIDES USING BENZOYL CYANIDE IN IONIC LIQUID
5
Ashok K. Prasad, Vineet Kumar, and Jyotirmoy Maity
Bioorganic Laboratory,
Department of Chemistry, University of Delhi, Delhi, India
5
Yogesh S. Sanghvi*
Isis Pharmaceuticals Inc., Carlsbad, California, USA
5
Vasulinga T. Ravikumar
Isis Pharmaceuticals Inc., Carlsbad, California, USA
Bioorganic Laboratory, Department of Chemistry, University of
5
Virinder S. Parmar
Delhi, Delhi, India
5
Use of benzoyl cyanide (BzCN) for benzoylation of nucleosides has been studied, both in pyridine
and in ionic liquid. BzCN in 1-methoxyethyl-3-methylimidazolium methanesulfonate as ionic liquid has
been found to be a ‘‘green’’ alternative compared to the pyridine-BzCN system. An efficient and selective
benzoylation of nucleosides of both, the 2’-deoxy- and the ribo-series at ambient temperature
was accomplished.
INTRODUCTION
One of the intrinsic problems, during the course of multistep synthetic
protocols in nucleic acid chemistry, is the selective manipulation of hydroxyl and
amino groups using labile protecting groups. This problem is further aggravated by
poor solubility of nucleosides in common organic solvents. One of the most
frequently used and preferred protecting groups for the protection of hydroxyl and
amino groups in nucleoside and nucleotide chemistry is the benzoyl group. This is
due to its less pronounced tendency to vicinal migration in comparison to acetyl
group.[1] The classical method for benzoylation of hydroxyl and amino groups is
treatment of the substrate with benzoyl chloride/benzoic anhydride in the presence
of pyridine, which usually requires extended time periods, elevated temperatures
This project was funded by ISIS pharmaceuticals Inc., CA. VK and JM thank CSIR, New Delhi, India, for the
award of Junior Research Fellowships to them.
*Current Address: Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92008, USA.
Address correspondence to Ashok K. Prasad, Bioorganic Laboratory, Department of Chemistry, University
of Delhi, Delhi 110 007, India.
747
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748
A. K. Prasad et al.
FIGURE 1
or time-consuming work-up procedure. Holy and Soucek[2] have demonstrated the
application of benzoyl cyanide (BzCN) in acetonitrile/dimethylformamide as a mild
benzoylating agent for the protection of nucleosides. However, these authors did
not study this reagent on all the eight natural 2’-deoxy- and ribonucleosides. Our
ongoing interest in acylation reactions on this class of compounds encouraged us to
expand and thoroughly investigate the application of BzCN as a suitable
benzoylation reagent.[3–7] Herein, we report results of benzoylation studies on
nucleosides of both, the 2’-deoxy- and the ribo-series using BzCN in pyridine and in
1-methoxyethyl-3-methylimidazolium methanesulfonate (MoeMIM.Ms) as an ionic
liquid (IL).
Benzoylation of Nucleosides Using BzCN in Pyridine as Solvent
Since most of the unprotected nucleosides are soluble in pyridine at high
concentrations, it was chosen as a solvent of choice. In a typical experiment,
nucleoside (1 mmol) was dissolved in pyridine (5 mL) and DMAP (10 mg) was
added, followed by the addition of BzCN (2.5–8.0 mmol). The reaction was stirred
at 40°C (at 115°C in case of 2’-deoxyguanosine and guanosine) and the progress
monitored by TLC. On completion, the reaction mixture was poured over crushed
ice while stirring in a fume hood. The precipitate was filtered off and washed with
water, followed by petroleum ether to afford benzoylated nucleosides as white
crystalline compounds in 11.0–96.5% yields. The results of benzoylation are
summarized in Figure 1.
FIGURE 2 1-Methoxyethyl-3-methylimidazolium methanesulphonate (MoeMIM.Ms).

A. K. Prasad et al.
749
TABLE 1
Starting
compd.
Reaction
time/temp
BzCN (equiv.)
Product(s)
Yield (%)*
HRMS Calcd./Obs.
1a
1b
1c
2.5
2.1
2.2
5 h/40°C
6 h/40°C
2 h/40°C
3a
3b
3c
3d
3d
3e
4a
4b
4c
4d
4e
94.0
93.0
79.3*
17.2*
96.5*
89.0
[M + H]+ 451.1505/451.1521
[M + H]+ 460.1621/460.1636
[M + H]+ 436.1509/436.1511
[M + H]+ 540.1771/540.1794
[M + H]+ 540.1771/540.1794
[M + H]+ 580.1832/580.1886
[M + H]+ 571.1717/571.1736
[M + Na]+ 602.1652/602.131
[M + Na]+ 682.1801/682.1901
[M + Na]+ 682.1801/682.1901
[M + Na]+ 722.1863/722.1981
1c
1d
2a
2b
8.0
6.0
5.0
6.0
2 h/40°C
4 h/115°C
3 h/40°C
5 h/40°C
89.0
71.5*
11.0*
92.0
2c
2d
6.8
7.0
7 h/40°C
7 h/115°C
88.5*
*The yields reported are on the basis of LC-MS analysis data.
Benzoylation of Nucleosides Using BzCN in Ionic
Liquid as Solvent
In recent years, room-temperature ILs have attracted much attention as the
‘‘green’’ solvents of the future. This is because of their negligible vapor pressure,
thermal stability, unprecedented ability to dissolve a broad range of compounds of
organic and inorganic nature and easy reuse. We have investigated the applications
of BzCN as benzoylating agent in the IL MoeMIM.Ms (Figure 2). This IL was
chosen as reaction medium (or solvent) because of its ability to dissolve a variety of
nucleosides[5] (Table 1).
In a typical experiment, nucleoside (1 mmol) was dissolved in MoeMIM.Ms
(1 ml) and catalytic amount of 4-DMAP was added, followed by the addition of
BzCN (2.5–3.5 mmol). The reaction mixture was stirred at room temperature (25–
30°C) and the progress monitored by TLC. On completion of the reaction, water
FIGURE 3

750
A. K. Prasad et al.
TABLE 2
Starting
compd.
BzCN
(equiv.)
Reaction
time
Product(s)
Yield (%)*
HRMS Calcd./Obs.
1a
1b
1c
2.5
2.5
2.5
1.5 h
2.0 h
2.5 h
3a
3b
3c
3d
3f
4a
4b
4g
4d
4h
92
91
68
10
65
96
85
70
12
70
[M + Na]+ 473.1325/473.1349
[M + Na]+ 482.1440/482.1441
[M + H]+ 436.1509/436.1511
[M + H]+ 540.1771/540.1804
[M + H]+ 476.1570/476.1601
[M + Na]+ 593.1536/593.1604
[M + H]+ 580.1832/580.1878
[M + H]+ 556.1720/556.1751
[M + Na]+ 682.1801/682.1901
[M + Na]+ 618.1601/618.1664
1d
2a
2b
2c
3.0
3.5
3.0
3.0
2.5 h
1.5 h
1.5 h
2.0 h
2d
3.5
2.5 h
*Isolated yields.
(20 ml) was added and the product extracted with ethyl acetate (3 Â 20 mL). The
organic layer was separated, dried over sodium sulfate, concentrated, and the
residue purified by silica gel column chromatography to afford the corresponding
O-benzoylated nucleosides as white solids in 65–96% yields; minor amounts of
perbenzoylated nucleosides were also obtained in case of 2’-deoxycytidine and
cytidine (Figure 3).
The benzoylation of nucleosides of 2’-deoxy- and ribo-series with BzCN in IL is
very selective and efficient as this combination exclusively/preferably benzoylated
the hydroxyl groups of the nucleosides over their amino group (Figure 3). One of
the major advantages of using IL in organic synthesis is that they are reusable. To
verify the reusability, the IL was recovered from the aqueous portion of the reaction
and used up to three cycles without any appreciable loss of its activity, except small
loss of the IL in handling. The structures of all benzoylated nucleosides were
1
unambiguously established on the basis of their spectral analysis (IR, H and 13C
NMR, and LC-MS) and comparison of their melting points and/or spectral data
with those reported in the literature (Ref. [7] and references therein, and Ref. [8])
(Table 2).
CONCLUSION
The benzoylation reaction carried out on 2’-deoxy- and ribo-series of nucleosides
with BzCN in pyridine was non-selective in most of the cases and required longer
reaction times, elevated temperature and led to the formation of corresponding
perbenzoylated products. Whereas, the BzCN in MoeMIM.Ms (IL) selectively/
preferentially benzoylated the hydroxyl groups over amino groups of nucleosides
at ambient temperature (25–30°C). Also we have demonstrated that IL was
recovered after benzoylation reactions. In conclusion, the ionic liquid MoeMIM.Ms
is found to be an improved and ‘‘greener’’ alternative to the hazardous conventional
solvents such as pyridine commonly employed in nucleoside chemistry.

A. K. Prasad et al.
751
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