5642
V. Kumar, S. V. Malhotra / Bioorg. Med. Chem. Lett. 18 (2008) 5640–5642
CF3COOH reacts together to form xenon (II) trifluoroacetate which
decomposes to give CO2 and CF3 radical which can attack at C-5 po-
sition of 6 to give 7.14 Similar reaction has been reported earlier
using excess of CF3COOH with 33% yield.14a When we carried out
this reaction in ILs, the yields are slightly higher and the compound
7 could be obtained up to 40% yield. The reason for lower conver-
sions in this reaction could be due to dimerization of highly reac-
tive CF3 radical to give hexafluoroethane gas. Finally the
References and notes
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2005, 8, 552; (c) Mathe, C.; Gosselin, G. Antiviral Res. 2006, 71, 276.
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M. Chem. Rev. 1992, 92, 1745.
3. (a) Wasserchied, W.; Kim, W. Angew. Chem., Int. Ed 2000, 39, 3772; (b) Zhao, H.;
Malhotra, S. V. Aldrichim. Acta 2002, 35, 75; (c) Jain, N.; Kumar, A.; Chauhan, S.;
Chauhan, S. M. S. Tetrahedron 2005, 60, 1015; (d) Malhotra, S. V.; Kumar, V.;
Parmar, V. S. Curr. Org. Synth. 2007, 4, 370; (e) Weingaertner, H. Angew. Chem.,
Int. Ed 2008, 47, 654; (f) Greaves, T.; Drummond, C. J. Chem. Rev. 2008, 108, 206.
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deprotection of
(Scheme 3).
7 using NH3/MeOH afforded trifluridine (8)
It is important to mention here that in all these cases, for
1 mmol scale reaction, 15–20 ml of molecular solvents are re-
quired, while only 1.5 ml of ILs were needed for the same scale
of reaction (due to the high solubility of substrate in ILs), i.e., there
is 10-fold decrease in the solvent consumption which makes the
use of ILs more viable and economical. Moreover, in all the sys-
tems, products were obtained with high purity as characterized
by 1H, 13C NMR spectra and LC HRMS data.
In conclusion, we have successfully synthesized nucleoside-
based antiviral drugs d4T, BVDU, and TFT using ionic liquids as
reaction medium. Ionic liquids proved to be superior solvents in
comparison of conventionally used solvents for nucleosides in
terms of solubility. Reactions in ILs proceed at much faster rate
and also the solvent requirement is reduced by 10-fold.
8. De Clercq, E. Med. Res. Rev. 2005, 25, 1.
9. Johar, M.; Manning, T.; Kunimoto, D. Y.; Kumar, R. Bioorg. Med. Chem. 2005, 13,
6663.
Acknowledgment
10. Ashwell, M.; Jones, A. S.; Kumar, A.; Sayers, J. R.; Walker, R. T.; Sakuma, T.; De
Clercq, E. Tetrahedron 1987, 43, 4601.
11. Carmine, A. A.; Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. Drugs
1982, 23, 329.
This project was funded by NCI Contract N01-CO-12400.
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Y.; Kinoshita, K.; Masuda, H.; Ishido, Y. Nucleosides Nucleotides 1996, 15,
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Supplementary data
Detailed experimental procedures, 1H NMR (400 MHz) and
13C NMR (101 MHz) data can be obtained from the supporting
information. Supplementary data associated with this article