Solid-phase synthesis (SPS) of substituted uracils via Oxone cleavage methodology

Article abstract of DOI:10.1016/S0040-4039(02)02380-8

An original and highly efficient Oxone cleavage methodology for the solid-phase synthesis of substituted uracils has been developed. An example of application of this methodology to the solid-phase synthesis of uridine derivatives is also reported.

Full text of DOI:10.1016/S0040-4039(02)02380-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9667–9670
Solid-phase synthesis (SPS) of substituted uracils via Oxone®
cleavage methodology
Elena Petricci, Michela Renzulli, Marco Radi, Federico Corelli* and Maurizio Botta*
Dipartimento Farmaco Chimico Tecnologico, Universita’ di Siena, via Aldo Moro, 53100 Siena, Italy
Received 12 September 2002; revised 17 October 2002; accepted 21 October 2002
Abstract—An original and highly efficient Oxone® cleavage methodology for the solid-phase synthesis of substituted uracils has
been developed. An example of application of this methodology to the solid-phase synthesis of uridine derivatives is also reported.
© 2002 Published by Elsevier Science Ltd.
Based on the growing interest in solid-phase
approaches to the synthesis of compound families and
taking into account the wide range of biological activi-
ties demonstrated by uracil derivatives,1–9 our efforts
were directed toward the development of a solid phase
methodology for obtaining substituted uracils.
Scheme 1.
* Corresponding author. Tel.: +39-0577-234306; fax: +39-0577-234333; e-mail: botta@unisi.it
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02380-8

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E. Petricci et al. / Tetrahedron Letters 43 (2002) 9667–9670
Scheme 2.
cleavage methodology. Some common methods of
thioether cleavage, such as reduction with sodium/
ammonia, acid catalyzed hydrolysis, or reaction with
heavy metal ion followed by treatment with hydrogen
sulfide,17 proved to be unsuccessful in our case, since no
uracil compound could be isolated from the reaction
mixture. Attempts to cleave the thioether function by
iodotrimethylsilane, which is commonly used in the
O-demethylation of alkoxypyrimidines18 and has
proven by us to be an effective reagent for the S-
demethylation of 2-methyl-4(3H)-pyrimidinones,19 or
by oxidation of the sulfide group to sulfoxide, followed
by Pummerer reaction,20 failed as well.21
In the past we focused our attention on an assembly
strategy performed in solution,10 which gave access to
5,6-disubstituted uracil compounds possessing interest-
ing biological activities. Although this methodology
provides a simple route to the target molecules, the
purification of these compounds is sometimes tedious
and limits their potential interest as intermediates in the
synthesis of more complex molecules. A solid-phase
approach to the synthesis of the target uracil derivatives
would allow to avoid the purification step and to
produce a large number of biologically interesting com-
pounds by means of combinatorial techniques. The
polymer-bound pyrimidinone nucleus 1, 2 (Scheme 1)
could in principle be easily derivatized, coupled with
sugars, or transformed into a polycyclic compound,
before being cleaved from the solid support.11–13
Finally, we found that Oxone® (potassium peroxy-
monosulfate), an efficient and selective oxidizing
agent,23 was a suitable reagent for the cleavage of
polymer-bound compounds 1, 2. Thus, swelling resin 1
in a solution of dioxane/water (6/1), followed by reflux-
ing for 12 h in the presence of 3 molar equivalents of
Oxone®, the desired products 5a–d were obtained
(Scheme 1). In order to drive reaction to completion,
the cleavage step was repeated twice under the same
experimental conditions to give highly pure substituted
uracils 5a–d in 78–98% yield (Table 1). When methanol
was used as solvent for the cleavage reaction, the
corresponding 2-methoxy derivatives 6a–d were
obtained in 67–95% yield.
In a previous note,2 we reported a successful solid-
phase synthesis of pyrimidinones 3a–c (Scheme 2),
where the pyrimidinone system was anchored to the
solid support (Merrifield resin) through a carbonate
moiety (see compound 4), which could be selectively
cleaved to afford the target compounds in good yield
and purity. As expected, we noticed that such a tetra-
methylene spacer was able to create a ‘chemical dis-
tance’ between the pyrimidinone nucleus and the
polymer backbone and to confer more ‘solution like’
properties and better solvent compatibility to the resin.
Moreover, it was of potential utility for the NMR
analysis of the polymer-bound compounds.14,15
Table 1. Uracil derivatives obtained with Oxone® cleavage
methodology using dioxane/H2O (compounds 5 a–d) or
methanol (compounds 6 a–d) as solvents
Based on these findings, the aim of the present work
was the solid-phase synthesis of different uracils by
cleavage of the thioether bond. However, in order to
avoid the formation of undesired products in the cleav-
age reaction, we decided to anchor the spacer to the
solid support through a more stable ether moiety
instead of the carbonate group. Accordingly, com-
pounds 1c–d and 2a–d (Scheme 1) were synthesized
following a procedure already described by us for the
preparation of compounds 1a,b.16
Compd
R
R%
Yield (%)
From 2
From 1
5a
5b
5c
5d
6a
6b
6c
6d
CH3
CH3
CH2Ph
CH2COOEt
CH3
CH3
CH2Ph
CH2COOEt
CH3
H
H
H
CH3
H
83
98
85
78
72
95
77
67
78
95
70
65
70
96
73
56
It is well known that n-alkyl thioethers are difficult to
be cleaved and hence have not been extensively used as
protecting groups; as a result, the most important issue
to be addressed was the identification of a suitable
H
H

E. Petricci et al. / Tetrahedron Letters 43 (2002) 9667–9670
9669
Scheme 3.
Acknowledgements
This original and highly efficient cleavage procedure
was also applied to the Wang resin supported pyrimidi-
nones 2 to afford compounds 5 and 6 in comparable
yields (Scheme 1, Table 1).
Italian National Research Council (CNR) ‘Progetto
Finalizzato Biotecnologie’ (CNR Target Project on
‘Biotechnology’) as well as the University of Siena
(PAR 2001) are gratefully acknowledged. M.B. wishes
to thank the Merck Research Laboratories for the 2001
Academic Development Program (ADP) Chemistry
Award.
The same procedure has been also applied to the paral-
lel synthesis of a small library of 12 uracil derivatives
using a Syncore® organic synthesizer at 200 rpm; sub-
stituted uracils (6-methyl; 6-benzyl; 6-trifluoromethyl;
6-ethyl; 6-isopropyl; 6-tert-butyl; 6-chloromethyl; 6-
adamantyl; 5-ethyl-6-methyl; 5-chloro-6-methyl; 5-
fluoro-6-methyl; ethyl 6-acetate) have been obtained in
yields ranging from 20 to 40%.
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