Fast and highly efficient one-pot synthesis of 9-deazaxanthines

Article abstract of DOI:10.1016/S0040-4039(03)00173-4

SnCl₂ enables a direct, high-yield conversion of 5-nitro-1,3-dialkyl-6-styryl(furyl-, thienyl-vinyl)-uracils to 8-substituted-9-deazaxanthines under very mild experimental conditions. The method has a general applicability and it is compatible with the reactivity of the most common organic functional groups. In slightly experimental different conditions, it allows a high-yield and fast (<5 min) preparation of pure 7-N-hydroxy-9-deazaxanthines.

Full text of DOI:10.1016/S0040-4039(03)00173-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2121–2123
Fast and highly efficient one-pot synthesis of 9-deazaxanthines
Angela Stefanachi,† Francesco Leonetti,† Anna Cappa and Angelo Carotti*
Dipartimento Farmaco-chimico, University of Bari, via Orabona 4, I-70125 Bari, Italy
Received 6 December 2002; revised 16 January 2003; accepted 16 January 2003
Abstract—SnCl2 enables a direct, high-yield conversion of 5-nitro-1,3-dialkyl-6-styryl(furyl-, thienyl-vinyl)-uracils to 8-substituted-
9-deazaxanthines under very mild experimental conditions. The method has a general applicability and it is compatible with the
reactivity of the most common organic functional groups. In slightly experimental different conditions, it allows a high-yield and
fast (<5 min) preparation of pure 7-N-hydroxy-9-deazaxanthines. © 2003 Elsevier Science Ltd. All rights reserved.
Recent studies indicate that adenosine receptor ligands
acting selectively on one of the four distinct receptor
subtypes (A1, A2A, A2B and A3), may be attractive
therapeutics in many pathophysiological conditions.1–4
co-workers20 reported an alternative synthetic protocol
to prepare 9-deazaxathines. Starting from 1,3,6-
trimethyl-5-nitro uracil, the final 9-deazaxanthines have
been obtained through an additional chemical step,
compared to the above cited methods. Moreover, such
a protocol, requiring the use of refluxing ethanolic
solution of 0.1 M KOH, presents a limited applicability
and it is unsuited for the preparation of chemical
libraries based on solid phase synthetic methodologies.
A huge number of adenosine receptor agonists and
antagonists have been synthesized and some of them
proved to be highly potent and subtype selective lig-
ands.5–9 Along with tricyclic condensed heterocycles,5–7
the most studied compounds are by far xanthine deriva-
tives, whereas 9-deazaxanthines10 and their 7 and 8-sub-
stituted derivatives,11,12 have received much less
attention.
Herein, we report a new, straightforward and high yield
synthesis of 9-deazaxanthines that overcomes most of
the drawbacks exhibited by previous procedures.
The target compounds were prepared in two simple
steps starting from a suitable 1,3-dialkyl-6-methyl-5-
nitrouracil11,12,17–19 that was condensed with appropri-
ate aldehydes in refluxing EtOH in the presence of
Despite their potential biological interest, the published
syntheses of these compounds are unsatisfactory in
terms of yields, reaction time, experimental conditions
and work up.
piperidine,
according
to
previously
reported
methods.10,17
Several approaches have been proposed so far for the
preparation of substituted 9-deazaxanthines.11,13–20 The
most widely used have been reported by Taylor17 and
Nishigaki.18 In Taylor’s scheme the cyclization of the
key 5-nitro-1,3-dialkyl-6-styryl-uracil intermediate is
obtained with neat triethyl phosphite17,19 at high tem-
perature, whereas in Nishigaki’s approach formic acid
and sodium dithionite18 have been used to accomplish
the same reaction. Both schemes showed two main
drawbacks: the yields of the cyclization reaction are low
(11–65%) and the experimental conditions used are very
harsh and often incompatible with the chemical stabil-
ity of many organic functional groups. Hirota and
Looking for a valuable procedure for the reductive
cyclization of uracil intermediates I (Scheme 1) to 9-
deazaxanthines, we planned to reduce first the nitro
group of the uracil moiety operating in mild conditions
and to perform then the subsequent cyclization reac-
tion. Since previous literature procedures reported that
the use of Pd/C, besides the reduction of the nitro
group afforded the undesired hydrogenation of the
styryl double bond,19 we decided to use a reducing
Lewis acid to carry out smoothly the reduction of the
nitro group. ZnCl2 gave no reduction of nitrouracils I
at room temperature. In contrast, SnCl2 in DMF not
only gave the reduction of the nitro group but
efficiently catalysed the subsequent cyclization afford-
ing the corresponding 7-N-hydroxy-9-deazaxanthine
derivatives 1–13 (Scheme 1).21
* Corresponding author. Tel.: ++39-080-5442782; fax: ++39-080-
5442230; e-mail: carotti@farmchim.uniba.it
† These authors contributed equally to this work.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00173-4

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A. Stefanachi et al. / Tetrahedron Letters 44 (2003) 2121–2123
Two main goals were reached in this way. First the
yield of the reaction was very high (from 95 to 99%)
and the compounds purity, as detected by NMR
analyses, was also very high. Second, the workup of
the reaction was very easy: the product was simply
recovered by filtering the solid obtained upon addi-
tion of water to the reaction mixture.
7-N-Hydroxy-9-deazaxanthines present, in comparison
with classical xanthines, an interesting chemical struc-
ture showing some peculiar pharmacophoric elements
for a good affinity (and possibly selectivity) towards
adenosine receptors. In addition, compared to simple
9-deazaxanthines they should posses more favorable
pharmacokinetic profile in terms of water solubility,
lipophilicity and bioavailability. To the best of our
knowledge no systematic work has been published on
the structure-affinity relationships of 7-N-hydroxy-9-
deazaxanthines towards the four main classes of
adenosine receptor subtypes. We are presently work-
ing on this subject.
The reaction was carried out also in different solvents
to study their influence in the reduction and cycliza-
tion processes. In DMSO the product was obtained in
yields and times comparable with DMF, while in
dioxane no detectable trace of the desired product
was found.
Starting from our encouraging results achieved in the
synthesis
of
7-N-hydroxy-9-deazaxanthines,
we
decided to evaluate the possibility to obtain easily
also 9-deazaxanthines in a way chemically amenable
to the preparation of chemical libraries of biological
interest. As suggested by Hirota,20 we tried to deoxy-
genate N-hydroxy-9-deazaxanthines 1–13 by heating
in DMF. Unfortunately, we failed to obtain the
desired compounds in good yields and purity as
claimed in that previous work.20
We tried next to accomplish the synthesis of these
compounds in a one-pot way starting from 1,3-
dialkyl-5-nitro-uracils. Satisfactorily indeed, by react-
ing uracil intermediates I with SnCl2 in refluxing
DMF for 2 h, the corresponding 9-deazaxanthines
14–26 were obtained in high yields (from 95 to 99%)
and purity (Scheme 2).22
In summary the methods described allow the synthe-
sis of 8-substituted-9-deazaxanthines and of the corre-
sponding 7-N-hydroxy derivatives in high yields and
in mild experimental conditions. As for the latter, the
reaction time (<5 min) and easily available reagents
used in the synthesis represent two important advan-
tages of our protocol compared with other published
ones. Furthermore, the approach proved to be of
general applicability, allowing us to accomplish the
synthesis of a large variety of 7-N-hydroxy-8-substi-
tuted-9-deazaxantines starting from aryl and het-
eroaryl aldehydes. Notably, good yields were obtained
with benzaldehydes bearing substituents with quite
different stereoelectronic properties. As for the syn-
thesis of 8-substituted-9-deazaxanthines, it must be
stressed that it can be carried out by a one-pot proce-
dure and in almost quantitative yields.
Scheme 1. Conversion of nitrouracil intermediates I into the
corresponding 7-N-hydroxy-9-deazaxanthines 1–13
Finally, preliminary data indicates that our methods
are fully compatible with a synthesis on solid phase,
and this may allow the preparation of 7-N-hydroxy-8-
substituted-9-deazaxanthine and 8-substituted-9-deaza-
xanthine libraries of biological interest, expanding the
scope and the utility of our synthetic procedures. Full
details of the preparation of both 7-N-hydroxy-9-
deazaxanthines and 9-deazaxanthines libraries will be
published in a forthcoming paper.
Scheme 2. One-pot synthesis of 9-deazaxanthines 14–26. R1
and R as in the corresponding sequence of 7-N-hydroxy
derivatives 1–13“14–26.

A. Stefanachi et al. / Tetrahedron Letters 44 (2003) 2121–2123
2123
Acknowledgements
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655–657.
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The authors gratefully acknowledge the financial sup-
port of the University of Bari (Italy), the Italian Min-
istry for Education, Universities and Research (MIUR,
Rome, Italy). A.S. thanks the European Community
for partially granting her Ph.D. fellowship.
20. Hirota, K.; Sugiyama, T.; Kitade, Y.; Senda, S.; Maki, Y.
J. Chem. Soc., Perkin Trans. 1 1984, 583–588.
21. 5-Hydroxy-1,3-dipropyl-6-p-tolyl-1,5-dihydro-pyrrolo-
[3,2-d] pyrimidine-2,4-dione 1. To a solution of 0.50 g (1.5
mmol) of 1,3-dipropyl-5-nitro-(2-p-tolyl-vinyl)-1H-pyrim-
idine-2,4-dione in 6 ml of DMF, 2.93 g (15 mmol) of
SnCl2 were added portion wise under magnetic stirring.
After 5 min, 6 ml of water were added to the reaction
mixture to yield a white solid that was filtered and
washed with water affording 0.45 g of the desired product
1 (99% yield) mp 233–234°C dec., IR cm−1: 3413, 2963,
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