The first synthesis of novel 7-oxo-7H-pyrrolo[3,2-d]pyrimidine 5-oxides from 1-(5-nitro-6-pyrimidinyl)-2-arylacetylenes

Article abstract of DOI:10.1055/s-2003-39883

Palladium-catalysed reaction of 4-amino-6-chloro-5-nitropyrimicline with arylacetylenes affords the corresponding 1-(4-amino-5-nitro-6-pyrimidinyl)-2-arylacetylenes, which in dry pyricline undergo smooth cyclisation to give 4-amino-6-aryl-7-oxo-7H-pyrrolo

Full text of DOI:10.1055/s-2003-39883

LETTER
1151
The First Synthesis of Novel 7-Oxo-7H-pyrrolo[3,2-d]pyrimidine 5-Oxides
from 1-(5-Nitro-6-pyrimidinyl)-2-arylacetylenes
T
he Firs
n
Synthesis
o
g
Novel 7-O
x
a
o-7
H
-pyrrolo[3,2
S
-
d
]
pyrimidine
u5-Oxides svilo, Algirdas Brukstus, Sigitas Tumkevicius*
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT-2006 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: sigitas.tumkevicius@chf.vu.lt
Received 13 February 2003
fluxed for 15 minutes in dry pyridine cyclisation occurred
to afford the corresponding dark violet colored pyrro-
lo[3,2-d]pyrimidine 5-oxides 3a–c in excellent yields
(Scheme 1).12
Abstract: Palladium-catalysed reaction of 4-amino-6-chloro-5-ni-
tropyrimidine with arylacetylenes affords the corresponding 1-
(4-amino-5-nitro-6-pyrimidinyl)-2-arylacetylenes, which in dry
pyridine undergo smooth cyclisation to give 4-amino-6-aryl-7-oxo-
7H-pyrrolo[2,3-d]pyrimidine 5-oxides in excellent yields.
NH2
NH2
Key words: catalysis, cyclisation, palladium, pyrimidines, pyrrol-
opyrimidines
NO2
Cl
NO2
N
i
N
N
N
The pyrrolo[3,2-d]pyrimidine heterosystem being 9-de-
azaanalogue of biogenic purine is an important class of
compounds possessing notable biological activities, in
particular purine nucleoside phosphorylase1 and thymi-
dylate synthase2 inhibitory, neuropeptide Y5 receptor3
and A1-, A2-adenosine receptor4 antagonistic properties.
One of the approaches for the construction of this ring sys-
tem is an annulation of a pyrrole ring onto an appropriate-
ly substituted pyrimidine. A literature survey revealed that
5-aminopyrimidines with suitable substituents are the
most often used starting compounds for this purpose5 and
there are only few reports on the straightforward synthesis
of pyrrolo[3,2-d]pyrimidines from 6-alkynylpyrimidines6
or 5-nitropyrimidines.7 The latter ones form pyrrolopyri-
midines usually under reductive cyclisation conditions.
However, to the best of our knowledge, no work has been
done on the synthesis of pyrrolo[3,2-d]pyrimidines from
5-nitropyrimidines bearing alkynyl substituents in the po-
sition 6 of the pyrimidine ring. In this context and as con-
tinuation of our ongoing program aimed on the synthesis
of the pyrimidine moiety containing heterosystems8 with
potential biological activity we report herein on the high-
yielding synthesis of the first representatives of pyrro-
lo[3,2-d]pyrimidine 5-oxides. The title compounds being
aza-analogues of isatogens are also believed to be poten-
tial traps for free radicals in biological milieu.9
1
2a–c
R
R
ii
-
NH2
N
O
+
N
2a, 3a: R = H
2b, 3b: R = Me
2c, 3c: R = F
N
O
3a–c
Scheme 1 Reagents: i)1-Arylacetylenes, PdCl2(PPh3)2, CuI, Et3N,
40 °C, Ar, 3 h; ii) pyridine, reflux, 15 min.
The structures of the synthesised compounds 2, 3 were
confirmed by their spectral and elemental analyses da-
ta.11,12 The IR spectra of 2a–c are characterised by the ab-
sorption of C≡C and NO2 groups at 2214–2210 cm–1 and
1582–1574 cm–1, respectively. The carbonyl stretching
frequency for 3a–c is observed in a region 1728–1724
cm–1. The mass spectra of 2a, 3a and 2b, 3b exhibited
molecular ions at m/z = 240 and 254, respectively. Ions at
m/z = 224 (M+ – O) and m/z = 196 (M+ – O – CO) as the
principle mode of fragmentation of molecular ion of 3a
were also recorded. The analogous fragmentation pattern
of M+ of compound 3b gave the ions (M+ – O) and (M+
– O – CO) at m/z = 238 and 210, respectively. The 1H and
13C NMR spectra exhibited the expected signals for the
particular groups.
For the synthesis of the title pyrrolo[3,2-d]pyrimidines an
easily available 4-amino-6-chloro-5-nitropyrimidine10 (1)
was chosen as starting material. Compounds 2a–c were
synthesised by the palladium-catalysed Sonogashira cou-
pling reaction of 1 with selected arylacetylenes.11 The best
yields of 2 were obtained when the reaction was carried
out in dry triethylamine under argone at 40 °C. When 1-
(5-nitro-6-pyrimidinyl)-2-arylacetylenes (2a–c) were re-
In conclusion, we have developed a relatively short and
efficient synthesis of new 4-amino-6-aryl-7-oxo-7H-pyr-
rolo[3,2-d]pyrimidine 5-oxides through palladium-cataly-
sed coupling reaction of 4-amino-6-chloro-5-
nitropyrimidine with arylacetylenes and subsequent cycli-
sation of the obtained 1-(5-nitro-6-pyrimidinyl)-2-aryl-
acetylenes. Extension of this method is currently
underway in our laboratories.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1151,1152,ftx,en;D03603ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1152
I. Susvilo et al.
LETTER
(10) Boon, W. R.; Jones, G. M.; Ramage, G. R. J. Chem. Soc.
Acknowledgement
1951, 96.
We express our gratitude to M. Kreneviciene and A. Karosiene for
the recording of NMR and IR spectra, to E. Kersuliene and M.
Gavrilova for the elemental analyses.
(11) Typical Procedure for the Preparation of 1-(4-amino-5-
nitro-6-pyrimidinyl)-2-arylacetylenes 2a–c. A mixture of
compound 1 (0.2 g, 1.15 mmol), PdCl2(PPh3)2 (0.016 g,
0.023 mmol), CuI (0.0022 g, 0.0115 mmol) and dry Et3N (10
mL) was stirred under Ar atmosphere for 1 min. Then the
corresponding arylacetylene (1.38 mmol) was added, the
mixture was flushed with Ar and heated under stirring at 40
°C for 3 h. After cooling to r.t. the precipitate was filtered off
and recrystallised to give compounds 2a–c.
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toluene). IR (nujol): nmax = 3328, 3237 (NH2), 1724 (CO)
cm–1. 1H NMR (DMSO-d6): d = 7.41–8.52 (5 H, m, Ar-H),
7.72 (1 H, br s, NH), 8.22 (1 H, br s, NH), 9.61 (1 H, s, C2H).
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toluene). IR (nujol): nmax = 3363, 3231 (NH2), 1728 (CO)
cm–1. 1H NMR (DMSO-d6): d = 2.4 (3 H, s, CH3), 7.41 (2 H,
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Synlett 2003, No. 8, 1151–1152 ISSN 1234-567-89 © Thieme Stuttgart · New York