A new and efficient one-pot synthesis of pyrido[2,1-f]purine-2,4-diones starting from 6-aminouracil derivatives

Article abstract of DOI:10.1055/s-2002-19342

A convenient synthesis of pyrido[2,1-f]purine-2,4-diones is described by reaction of 6-aminouracil derivatives with N-bromosuccinimide (NBS) followed by in situ reaction with pyridine or 4-substituted pyridines. A detailed study of the reaction conditions has been performed and a mechanism involving a 5,5-dibromo derivative is proposed.

Full text of DOI:10.1055/s-2002-19342

LETTER
155
A New and Efficient One-pot Synthesis of Pyrido[2,1-f]purine-2,4-diones
Starting from 6-Aminouracil Derivatives
A
nNew and Efficient
a
One-pot Sy
r
nthesis
o
í
f
P
yrid
a
o[2,1-
f
]pur
-
J
ione
s
esús Pérez-Pérez,* Eva-María Priego, María-Luisa Jimeno, María-José Camarasa
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)5644853; E-mail: mjperez@iqm.csic.es
Received 22 October 2001
O
N
O
O
N
Abstract: A convenient synthesis of pyrido[2,1-f]purine-2,4-di-
ones is described by reaction of 6-aminouracil derivatives with N-
bromosuccinimide (NBS) followed by in situ reaction with pyridine
Br
N
N
HN
HN
HN
+
O
O
N
NH2
O
NH2
or 4-substituted pyridines. A detailed study of the reaction condi-
tions has been performed and a mechanism involving a 5,5-dibromo
derivative is proposed.
Ph
Ph
Ph
3
1
2
Scheme 1
Key words: heterocycles, tricyclic compounds, pyridines, haloge-
nation, N-bromosuccinimide
The only previous records that we could find of this type
of structures were related to a Pfizer patent.9 The proce-
dure there described involved a two step synthesis starting
from 6-chloro-1,3-dimethyluracil that reacted with 2-ami-
nopyridines in the presence of NaH followed by heating
with thionyl chloride. This methodology has also been
employed by Gatta et al.10 on 1,3-dipropyl-6-aminouracil.
Since our reaction conditions clearly differ from the pre-
vious records on this type of structure, we considered of
interest to study this reaction in detail. The results ob-
tained are reported in this communication.
6-Amino-5-bromouracil derivatives are interesting chem-
ical entities both from a chemical and a pharmacological
point of view. They are the reference inhibitors of an en-
zyme involved in the nucleoside salvage pathway, thymi-
dine phosphorylase, nowadays profusely studied as an
angiogenic agent.1,2 Moreover, 6-amino-5-bromouracil
derivatives have been used as intermediates in the synthe-
sis of xanthine derivatives,3,4 compounds that have been
an active area of research, already for many years, due to
their pharmacological properties as adenosine antagonists
or phosphodiesterase inhibitors.5
Initially, varying amounts of NBS in pyridine were as-
sayed (Table 1). Thus, treatment of 6-amino-1-benzylu-
racil 1 with 0.9 equivalents of NBS in pyridine at 80 ºC
(entry 1) afforded, exclusively, the 5-bromo derivative 2
in 74% yield. On the other hand, when 2.5 equivalents of
NBS were employed, also in pyridine at 80 ºC (entry 2),
the major compound obtained was the tricyclic derivative
3 (65%) with the 5-bromo derivative 2 being the minor
compound. Alternatively, treatment of the 5-bromo deriv-
ative 2 with 1.5 equivalents of NBS in pyridine at 80 ºC
(entry 3) afforded the tricyclic derivative 3 in 68% yield.
It should also be mentioned that heating of the 5-bromo
derivative 2 in pyridine, in the absence of NBS, even after
long periods, left the 5-bromo derivative unaltered. These
very simple experiments indicated that the 5-bromo deriv-
ative 2 is an intermediate for the formation of 3 in the re-
action of 1 with excess NBS in pyridine. Under these
reaction conditions no other intermediates could be de-
tected, although the course of the reaction was not easy to
follow due to extensive precipitation.
Bromination of 6-aminouracil derivatives has been most-
ly performed by reaction with bromine either in acetic
acid in the presence of alkali metal acetates, or in water or
methanol in the presence of alkali metal carbonates or bi-
carbonates.3,6 N-Bromosuccinimide (NBS) is a good alter-
native to avoid the irritating bromine as described by
Pfleiderer and coworkers.3 In the course of our research
programme on thymidine phosphorylase inhibitors,2,7 we
were interested in brominating several 6-aminouracil de-
rivatives. We chose NBS as a brominating agent, and py-
ridine as the solvent, considering that its basicity should
favour the solubility of the 6-aminouracils. Thus, reaction
of 6-amino-1-benzyluracil3 1 with 1.2 equivalents of NBS
in pyridine at 80 ºC afforded the expected 6-amino-1-ben-
zyl-5-bromouracil3 2 in 70% yield (Scheme 1). However,
a second strong UV absorption product was also detected
and isolated in 15% yield. This minor compound was
identified as 1-benzyl-1H,3H-pyrido[2,1-f]purine-2,4-di-
one 3. Its structure were unequivocally determined by 1H
NMR, 13C NMR, HMQC and HMBC experiments, and its
elemental composition was established by mass spec-
trometry and combustion analysis.8
Table 1 Reaction of 6-Amino-1-benzyluracil Derivatives with
varying Amounts of NBS in Pyridine
Entry
Substrate
Equivalents NBS Product (Yield)
1
2
3
1
1
2
0.9
2.5
1.5
2 (74%)
3 (65%) + 2 (< 10%)
3 (68%) + 2 (< 10%)
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0155,0157,ftx,en;G31001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

156
M.-J. Pérez-Pérez et al.
LETTER
In order to increase the solubility of the substrates in- It should be added that, when compound 4 was treated
volved, the same reaction sequences were performed on with 2.5 equivalents of N-chlorosuccinimide in acetoni-
6-amino-1-benzyl-3-propyluracil 4. This compound was trile, a compound with Rf value similar to 7 was detected
prepared from 1 following our recently described on TLC (tentatively it should correspond to the 5,5-
procedure to alkylate 6-aminouracil derivatives via N- dichloro analogue of 7). Addition of pyridine and heating
[(dimethylamino)methylene]6 protection.11 Treatment of lead to the transformation of this spot into the fused xan-
411 with 0.9 equivalents of NBS in pyridine afforded the thine 6, although, this transformation was slower than in
5-bromo derivative 5 in 77% yield12 (Scheme 2). On the the case of the 5,5-dibromo derivative 7.
other hand, reaction of 4 with 2.5 equivalents of NBS in
From all the described experiments above, it is clear that
the tricyclic derivative 6 is obtained by reaction of the 5,5-
dihaloderivative with pyridine. Upon searching for previ-
ous records on reaction of dihaloderivatives with pyridine,
pyridine afforded the fused xanthine 6 (42% yield),13 to-
gether with the 5-bromoderivative (5, 30% yield). So, the
behaviour of 4 is quite similar to that observed for 1 under
the same reaction conditions. It was also clear that in the
quite close examples were found, described by Taylor16
formation of 6, pyridine was behaving not only as the sol-
and later on by Kappe,17 on reaction of 5,5-dihalobarbitu-
ric acids with pyridine to yield ylides. Based on these pre-
cedents, a tentative mechanism, which is outlined in
vent but also as a reagent. Therefore, pyridine was re-
placed by acetonitrile as solvent. Thus, reaction of 4 with
2.5 equivalents of NBS in acetonitrile at 80 ºC afforded a
new product 7, that on TLC had Rf value higher than those
of the already identified compounds 5 and 6. Addition of
pyridine (5–10 equiv) to the reaction mixture, allowed
transformation of this spot 7 into the fused xanthine 6 to-
gether with the concomitant formation of the 5-bromo de-
Scheme 3, is proposed. Following a pathway analogous to
that proposed by Taylor16 (pathway A), the reaction
should be initiated by nucleophilic attack of pyridine to
the dihaloderivative A, displacing a halonium ion and giv-
ing rise to the anion B, which reacts with pyridine to dis-
place a halide ion and generate intermediate C.
rivative 5. This new product 7 could be isolated as a glassy
Alternatively, and following Kappe’s proposal17b (path-
syrup, although it tends to decompose.14,15 The mass
way B), the first step should involve the nucleophilic sub-
spectrum of 7 indicated a dibrominated compound with a
stitution of one halogen atom by pyridine to generate D,
quasimolecular peak pattern of 416, 418 and 420. The 1H
that, by elimination of X2, should give the same interme-
NMR spectrum of 7 showed the disappearance of the NH2
diate C. In such an intermediate C, the positive charge in
signal at 4.88 ppm (compared to 5) and the appearance of
the pyridine facilitates a nucleophilic attack in the -posi-
an NH at 9.59 ppm. The 13C NMR spectrum of 7 showed
tion to of the pyridine to generate E,19 that aromatizes to
a signal at 50.58 ppm, that based on long-range correla-
tion experiments was assigned as the C-5 of the pyrimi-
yield the final pyrido[2,1-f]purine-2,4-diones (F).
dine. The upfield shift of this carbon atom ( = –22.6
O
O
O
ppm, compared to 5) is compatible with the presence of a
second bromo at position 5, therefore the amino at posi-
tion 6 should now be an imine instead of an enamine as in
5. Indeed, the 15N NMR spectrum of 7 confirmed the pres-
ence of an imine by a signal shielded 145 ppm with re-
spect to nitromethane (reference signal).
X
X
Pathway A
X
X
+
N
X
NH
NH
NH
A
N
B
Pathway
N
B
X
O
O
X
O
X
X2
X
N
N
Br
+
N
N
NH
NH
O
N
NH2
D
C
N
H
Ph
X
5
a
O
N
O
N
O
b
N
N
O
N
N
N
N
5
+
O
NH2
O
N
N
Ph
Ph
N
c
4
H
6
E
F
O
N
Scheme 3
Br
Br
d
6
+
5
O
NH
Based on the mentioned results above, the experimental
conditions were changed to facilitate the follow up of the
reaction and isolation of the final compounds. The syn-
thetic procedure of choice is a two-step, one-pot reaction
that consists of the generation of the 5,5-dibromo com-
pound in acetonitrile, followed by addition of pyridine
and heating for 4–6 hours to generate the fused xan-
Ph
7
Scheme 2 a) 0.9 equiv NBS/pyridine/80 ºC, 5 (77%); b) 2.5 equiv
NBS/pyridine/80 ºC, 6 (42%) and 5 (30%); c) 2.5 equiv NBS/CH3CN/
80 ºC, 7; d) 5 equiv pyridine/80 ºC, 6 (42%) and 5 (30%)
Synlett 2002, No. 1, 155–157 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New and Efficient One-pot Synthesis of Pyrido[2,1-f]purine-2,4-diones
157
thines.18 Following this synthetic procedure, attempts
were made to extend this reaction to other pyridines.
Treatment of the 5,5-dibromo compound 8, generated in
situ, with 2-methoxy, 2-cyano or 2-bromopyridine, failed
to afford the corresponding fused xanthines. It could be
argued that the steric demands on the 2-substituted py-
ridines prevent reaction at the hetero nitrogen atom.16
However, when the reaction was performed by the addi-
tion of 4-t-butyl or 4-methoxypyridine, the expected fused
xanthines 9 and 10 were obtained in 58% and 74% yield,
respectively (Scheme 4).
(8) Selected data of 3: Mp (CH2Cl2–MeOH): 298–299 °C. MS
(EI): m/z = 292 [M+]. 1H NMR (DMSO-d6): 5.22 (s, 2 H,
CH2Ph), 7.10–7.50 (m, 6 H, H-7, Ph), 7.66 (m, J = 7.1, 1.2
Hz, H-8), 7.75 (d, J = 9.1 Hz, 1 H, H-9), 8.94 (d, J = 6.6 Hz,
H-6), 11.35 (br s, 1 H, NH). 13C NMR (DMSO-d6): 44.92
(CH2Ph), 101.95 (C-4a), 114.51 (C-7), 116.08 (C-9), 127.11,
127.20, 128.32, 136.71 (C-6, Ph), 130.34 (C-8), 147.08 (C-
9a), 150.85 (C-10a), 151.60 (C-2), 154.53 (C-4). Anal.
Calcd for C16H12N4O2: C, 65.75; H, 4.14; N, 19.17; found: C,
65.47; H, 4.50; N, 19.35.
(9) Chem. Abstr. 1970, 72, 12771b.
(10) Gatta, F.; Del Giudice, M. R.; Borioni, A.; Mustazza, C. J.
Heterocycl. Chem. 1994, 31, 81.
(11) Priego, E. M.; Camarasa, M. J.; Pérez-Pérez, M. J. Synthesis
2001, 478.
R
(12) Selected data of 5: MS (ES, positive mode): m/z = 360, [M +
Na+], showing the Br isotopic pattern. 1H NMR (CDCl3):
0.97 (t, 3 H, CH3CH2), 1.72 (m, 2 H, CH3CH2), 4.00 (m, 2 H,
NCH2), 4.97 (br s, 2 H, NH2), 5.28 (s, 2 H, CH2Ph), 7.26–
7.43 (m, 5 H, Ph). 13C NMR (CDCl3): 11.32 (CH3CH2),
21.11 (CH3CH2), 44.40 (NCH2), 47.78 (CH2Ph), 73.25 (C-
5), 150.40, 150.93 (C-2, C-6), 158.52 (C-4).
O
N
O
N
O
N
Br
Br
NH
R
N
HN
HN
N
HN
2
+
O
NH2
O
O
N
Ph
Ph
9 R = t-Bu
8
1
Ph
10 R = OCH3
(13) Selected data of 6: Mp (CH2Cl2–MeOH): 163–165 °C. MS
(EI): m/z = 334 [M+]. 1H NMR (CDCl3): 0.95 (t, J = 7.5 Hz,
3 H, CH3), 1.69 (m, J = 7.5 Hz, 2 H, CH2CH3), 4.01 (pt,
J = 7.3 Hz, 2 H, NCH2), 5.37 (s, 2 H, CH2Ph), 7.06 (pt,
J = 6.1 Hz, H-7), 7.25–7.52 (m, 5 H, Ph), 7.52 (pt, J = 7.0
Hz, H-8), 7.65 (d, J = 7.0 Hz, 1 H, H-9), 9.04 (d, J = 6.7 Hz,
1 H, H-6). 13C NMR (CDCl3): 11.32 (CH3CH2), 21.38
(CH3CH2), 42.83 (NCH2), 46.67 (CH2Ph), 101.90 (C-4a),
113.90 (C-7), 116.41 (C-9), 127.48 (C-6), 129.87 (C-8),
147.63 (C-9a), 150.69 (C-10a), 151.39 (C-2), 155.01 (C-4).
Anal. Calcd for C19H18N4O2: C, 68.25; H, 5.43; N, 19.76;
found: C, 68.19; H, 5.12; N, 19.40.
(14) Selected data of 7: MS (ES, positive mode): m/z = 416 [M +
1]+, showing the isotopic 2 Br pattern. 1H NMR (CDCl3):
0.97 (t, 3 H, CH3CH2), 1.67 (m, 2 H, CH3CH2), 3.90 (m, 2 H,
NCH2), 5.31 (s, 2 H, CH2Ph), 7.28–7.49 (m, 5 H, Ph), 9.59
(br s, 1 H, NH). 13C NMR (CDCl3): 10.94 (CH3CH2), 20.68
(CH3CH2), 45.38 (NCH2), 48.40 (CH2Ph), 50.58 (C-5),
149.14 (C-2), 156.52 (C-6), 161.05 (C-4).
Scheme 4
In summary, a simple, satisfatory and unusual synthesis of
pyrido[2,1-f]purine-2,4-diones has been performed by re-
action of 6-aminouracil derivatives with NBS in the pres-
ence of pyridine or 4-substituted pyridines. According to
the results here presented, the reaction pathway involves
the formation of 5,5-dibromo derivatives that further react
with the corresponding pyridine. In this way, the pyri-
do[2,1-f]purine-2,4-diones are easily and smoothly ob-
tained, and their biological evaluation is underway.
Acknowledgement
Financial support from the Spanish CICYT (SAF 2000-0153-C02-
01) is gratefully acknowledged.
(15) The dibromination of 6-amino-1-methyluracil has been
proposed in the synthesis of pyrimidin-5-yl sulphides and
disulphides: Barker, G. R.; Luthy, N. G. J. Chem. Soc. 1956,
917.
(16) Taylor, E. C. Jr.; Paudler, W. W.; Cain, C. K. J. Org. Chem.
1955, 20, 264.
(17) (a) Peichl, E.; Kappe, T. Arch. Pharm. 1984, 317, 946.
(b) Kappe, T.; Khorchid-Zadeh, R.; Steininger, H. Z.
Naturforsch. 1975, 30b, 773.
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heated at 80 ºC for 1 h till all starting material was
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Synlett 2002, No. 1, 155–157 ISSN 0936-5214 © Thieme Stuttgart · New York