Versatile, convenient synthesis of pyrimido[1,2,3-cd]purinediones

Article abstract of DOI:10.1016/S0040-4020(02)01485-0

The alkylation of 3-substituted cycloalkylcarboxamido-6-aminouracil derivatives with 3-bromo-1-propanol followed by ring closure yields 1,3,8-trisubstituted xanthine derivatives bearing a polar hydroxyl group. Use of the more reactive 1,3-dibromopropane or homologous dibromoalkanes for the alkylation reaction results in simultaneous alkylation at N1 and the exocyclic amino group (N⁶) yielding imidazo-, pyrimido- and diazepino-pyrimidine derivatives. The pyrimidopyrimidine derivatives can subsequently be cyclised using hexamethyldisilazane at high temperature affording an easy, convenient and general access to tricyclic pyrimido[1,2,3-cd]purinediones. Alternatively, 3-substituted 6-amino-5-benzylideneaminouracil derivatives can be reacted with 1,3-dibromopropane followed by an oxidative cyclisation using thionyl chloride to obtain the desired tricyclic pyrimido[1,2,3-cd]purinediones, which are sterically fixed analogues of pharmacologically active purine derivatives.

Full text of DOI:10.1016/S0040-4020(02)01485-0

Tetrahedron 59 (2003) 47–54
Versatile, convenient synthesis of pyrimido[1,2,3-cd]purinediones
*
¨
Stefanie Weyler, Alaa M. Hayallah and Christa E. Muller
¨
Pharmazeutisches Institut, Pharmazeutische Chemie Poppelsdorf, Universitat Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany
Received 20 August 2002; revised 9 November 2002; accepted 15 November 2002
Abstract—The alkylation of 3-substituted cycloalkylcarboxamido-6-aminouracil derivatives with 3-bromo-1-propanol followed by ring
closure yields 1,3,8-trisubstituted xanthine derivatives bearing a polar hydroxyl group. Use of the more reactive 1,3-dibromopropane or
homologous dibromoalkanes for the alkylation reaction results in simultaneous alkylation at N1 and the exocyclic amino group (N6) yielding
imidazo-, pyrimido- and diazepino-pyrimidine derivatives. The pyrimidopyrimidine derivatives can subsequently be cyclised using
hexamethyldisilazane at high temperature affording an easy, convenient and general access to tricyclic pyrimido[1,2,3-cd]purinediones.
Alternatively, 3-substituted 6-amino-5-benzylideneaminouracil derivatives can be reacted with 1,3-dibromopropane followed by an
oxidative cyclisation using thionyl chloride to obtain the desired tricyclic pyrimido[1,2,3-cd]purinediones, which are sterically fixed
analogues of pharmacologically active purine derivatives. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
xanthine derivatives to which a third ring is attached
bridging the N3- and N9-positions (Fig. 2).
The pyrimidine and purine ring systems undoubtedly belong
to the most ubiquitous heterocycles in nature, as they
represent the main structure of many biologically significant
compounds, including nucleosides and nucleotides.
Since 1,3,8-trisubstituted xanthines with various substitu-
ents are known as highly potent antagonists for adenosine
receptors,8 4,5-dihydro-6H,8H-pyrimido[1,2,3cd]purine-
8,10(9H)-diones might be potential new lead structures for
novel adenosine receptor ligands.
For this reason many analogues and derivatives of purine
and pyrimidine have been synthesised and developed as
pharmacologically active compounds or drugs.1
The activity and selectivity of the xanthine derivatives and
other adenosine receptor ligands towards the different
adenosine receptor subtypes is largely influenced by their
substitution pattern. For this reason variation in positions 2
and 9 of 4,5-dihydro-6H,8H-pyrimido[1,2,3-cd]purine-
8,10(9H)-diones, which are corresponding to position 1
and 8 of xanthines (Fig. 2) is very important. Up to now the
synthesis of only few 2,9-disubstituted 4,5-dihydro-6H,8H-
pyrimido[1,2,3-cd]purine-8,10(9H)-diones has been
reported in the literature,9–11 namely such with a methyl
substituent in position 99,10 and one derivative with a propyl
residue in that position. The latter was identified as a side
product in the bromination reaction of 8-cyclopropyl-3-(3-
hydroxypropyl)-1-propylxanthine at the hydroxypropyl
group.11 The above synthesis which yielded 9-methyl
derivatives,9,10 started from 6-chloro-3-methyl-5-nitro-
uracil. This starting material is difficult to prepare by a
3-step synthesis giving only moderate yields.12
Pharmacologically active purine analogues include tricyclic
structures such as imidazo[2,1-i]purinones (e.g. PSB-11, a
potent A3 adenosine receptor antagonist),2 pyrimido[4,5-
b]indoles (e.g. APEPI, a potent A1 adenosine receptor
antagonist)3 and imidazo[2,1-a]purines (e.g. tricyclic gan-
ciclovir analogues, which are potent antiviral agents)4,5
(Fig. 1). In general, cyclisation of a molecule results in a
reduction of conformational flexibility. Such a rigid fixed
conformation may result in an increased affinity to a target
structure, if the cyclised structure resembles the bioactive
conformation. A well known example is etorphine, a
morphine derivative, which contains an additional aliphatic
six-membered ring and shows an activity which is 1000-fold
higher than that of morphine itself.6,7 We have now
developed a novel, versatile and convenient approach to
2,9-disubstituted 4,5-dihydro-6H,8H-pyrimido[1,2,3-
cd]purine-8,10(9H)-diones, which can be envisaged as
The newly developed synthetic procedure to obtain 2,9-
disubstituted 4,5-dihydro-6H,8H-pyrimido[1,2,3cd]purine-
8,10(9H)-diones allows to easily diversify the substituents
in the positions 2 and 9. A recently developed general
synthesis of 1,3,8-substituted xanthines13 (Scheme 1) was
applied and modified to give the desired products.
Keywords: pyrimido[1,2,3-cd]purinediones; xanthine derivatives; tricyclic
purine derivatives; pyrimido[1,6-a]pyrimidines; ring closure reaction.
*
Corresponding author. Tel.: þ49-228-732301; fax: þ49-228-732567;
e-mail: christa.mueller@uni-bonn.de
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01485-0

48
S. Weyler et al. / Tetrahedron 59 (2003) 47–54
Figure 1. Examples of pharmacologically active tricyclic purine deriva-
tives and analogues.
2. Syntheses
2.1. Synthesis of 1,3,8-trisubstituted xanthines
Scheme 1. Synthetic route for 1,3,8-trisubstituted xanthines.
Initially we prepared 3-hydroxyalkylxanthine derivatives
bearing suitable 1-(propyl, butyl) and 8-substituents (phe-
nyl, cycloalkyl) to obtain high A1 adenosine receptor
affinity (Scheme 1). The hydroxyl function was required
(i) to increase hydrophilicity and hence water-solubility,
which is an important prerequisite for pharmacological
activity, and (ii) as a functional group which could be used
for prodrug formation or for the attachment of photoaffinity,
fluorescence, or other labels.
reaction was stopped by the addition of water. Replacement
of potassium carbonate by sodium or caesium carbonate as a
base did not increase the yields of the alkylation reaction.
The subsequent ring closure to obtain the desired 1,3,8-
trisubstituted xanthines 4b,c,e was carried out under reflux
either with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) in the
presence of catalytic amounts of ammonium sulphate or
with 10% aqueous sodium hydroxide solution in methanol.
The yields were similar with both methods for 8-
cyclopentylxanthines, while the latter method could not be
employed for the preparation of the 8-(3-noradamantyl)-
xanthine derivative 4e since it was too aggressive, resulting
in N1-dealkylation, and amide 2e was recovered. Only with
the milder method using HMDS the desired 1-butyl-3-(3-
hydroxypropyl)-8-(3-noradamantyl)xanthine (4e) could be
obtained (Scheme 2).
The general synthesis of 1,3,8-trisubstituted xanthines starts
from 3-substituted 5,6-diaminouracils 1a,b, which can be
obtained by standard procedures.14 The compounds 1a and
1b were treated with cycloalkyl carboxylic acids or benzoic
acid in methanol in the presence of N0-(3-dimethylamino-
propyl)-N-ethylcarbodiimide-hydrochloride (EDC) to
obtain the corresponding amides 2a–e.15 In the next step,
these amides 2a–e were dissolved in dry dimethylforma-
mide (DMF) in the presence of dry potassium carbonate,
and alkylation in position 1 was performed with 3-bromo-1-
propanol in analogy to procedures described in the
literature.13,16
2.2. New approach to 2,9-disubstituted 4,5-dihydro-
6H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-diones
In analogy to the presented synthetic route for the
preparation of 3-(3-hydroxypropyl)-substituted xanthine
derivatives, the synthesis of 2,9-disubstituted 4,5-dihydro-
6H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-diones was
started from 3-substituted 4,5-diaminouracils 1a,b. 3-Propyl-
and 3-butyl-5,6-diaminouracil 1a,b were prepared accord-
ing to published procedures in high yields.14 A variety of
other substituents, such as saturated and unsaturated alkyl
residues or substituents containing an aromatic structure,14
can also be easily introduced thus allowing a broad variation
in the 9-position (R1) of the final product. Subsequently, the
5,6-diaminouracils 1a,b were transferred to the correspond-
ing amides 2a–e as described above for the preparation of
xanthines. In the next step, the additional six-membered ring
was introduced by treatment with 1,3-dibromopropane in
DMF in the presence of potassium carbonate. 1,3-Dibro-
mopropane is highly reactive and does not only react with
the nitrogen in position 1 of the uracil, as 3-bromopropanol
does, but also with the amino group attached to position 6 to
This hydroxyalkylation was the most difficult step in the
synthetic route as the yields were generally low (34–43%).
All reagents had to be dry and the reaction had to be
performed under an argon atmosphere. Besides this, the
progress of the reaction was difficult to monitor by TLC due
to very similar Rf values of educts and products in common
organic solvents. Only after the addition of a few drops of
ammonia to the solvent (dichloromethane–methanol), the
product spot could be separated from the educt. Finally, the
Figure 2. Structures and numbering of uracil, xanthine and 4,5-dihydro-
6H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-dione.

S. Weyler et al. / Tetrahedron 59 (2003) 47–54
49
Scheme 2. Synthetic route for 2,9-disubstituted 4,5-dihydro-6H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-dione.
give the bicyclic structure 5a–e. These products could be
1
identified by their H NMR-spectra: the signal of the 6-
good yields. The final ring closure could not be carried out
with other condensing agents, which are generally used in
xanthine synthesis, such as aqueous-methanolic sodium
hydroxide or methanolic sodium methylate solution. The
imidazo[1,2-c]pyrimidine derivative 9c and also the pyr-
imido[1,6-a][1,3]diazepine derivative 10c could not be
cyclised with any of these methods presumably because
the expected products of the ring closure are energetically
unfavourable.
amino group of compound 2a–e is shifted downfield in
compound 5a–e and corresponds to only one proton.
Furthermore the structures of 5a–e were confirmed by high
resolution mass spectra. Using a 3-fold excess of 1,3-
dibromopropane the desired products 5a–e were obtained in
yields of about 50%.
As these yields were quite satisfactory for alkylation
reactions involving an intramolecular cyclisation, the
method was also examined with homologous dibromoalk-
ane derivatives, including 1,2-dibromoethane, 1,4-dibromo-
butane, 1,5-dibromopentane, 1,6-dibromohexane and 1,8-
dibromooctane. It was found that the analogous intramole-
cular reaction took place with 1,2-dibromoethane yielding
compound 9c containing a five-membered ring, and with
1,4-dibromobutane yielding a seven-membered ring 10c.
However, with the higher homologues no ring closure could
be obtained under the same conditions (Scheme 3).
An alternative procedure was explored to prepare the
tricyclic compound 9-butyl-2-phenyl-4,5-dihydro-6H,8H-
pyrimido[1,2,3-cd]purine-8,10(9H)-dione (6a). The 5,6-
diaminouracil derivative 1a was reacted in high yields
with benzaldehyde to obtain 6-amino-5-(benzylidenea-
mino)-3-butyl-(1H)-pyrimidine-2,4-dione (7a).17 This com-
pound could be converted to the bicyclic product 8a by
reaction with 1,3-dibromopropane in analogy to the
preparation of the amide derivatives 5a–e. The final ring
closure was achieved oxidatively with thionyl chloride as
reagent and solvent,18 to give the tricyclic product 6a in
good yield.
Treatment of the bicyclic six-membered products 5a–e with
HMDS gave the desired disubstituted tricyclic 4,5-dihydro-
6H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-diones 6a–e in
Preliminary radioligand binding studies indicated that the 2-
noradamantyl-substituted
pyrimido[1,2,3-cd]purine-
8,10(9H)-diones 6d and 6e exhibit high, nanomolar affinity
and selectivity for the A1-adenosine receptor. Comprehen-
sive pharmacological in vitro investigations of the new
compounds are currently in progress.
3. Conclusions
In conclusion, we have developed novel approaches to 2,9-
disubstituted 4,5-dihydro-6H,8H-pyrimido[1,2,3-cd]purine-
8,10(9H)-diones, which allow the introduction of a variety
of substituents in position 2 via aldehydes or carboxylic
acids and in position 9 by a convenient alkylation reaction.
The tricyclic purine derivatives are of interest as
potential new lead structures in drug development. The
Scheme 3. Preparation of imidazo[1,2-c]pyrimidine derivative 9c and
pyrimido[1,6-a][1,3]diazepine derivative 10c.

50
S. Weyler et al. / Tetrahedron 59 (2003) 47–54
3-(3-hydroxypropyl)xanthines, obtained by a recently
developed method, may be useful as functionalized
adenosine receptor antagonists.
Calcd for C15H18N4O3: %C, 59.59; %H, 6.00; %N, 18.53.
Found: %C, 59.50; %H, 6.00; %N, 18.51.
4.2.2. 6-Amino-5-cyclopentanecarboxamido-2,4-dioxo-3-
propyl-1,2,3,4-tetrahydropyrimidine (2b). Yield: 0.84 g
(60%, lit. yield: 93%15). Mp 2928C (lit. mp .3008C15). 1H
NMR and 13C NMR are identical to the data given in
literature.15
4. Experimental
4.1. General
NMR spectra were recorded on a Varian XL-300 (1H:
300 MHz, 13C: 75 MHz) or a Bruker DRX 500 (1H:
500 MHz, 13C: 125 MHz). Deuterated DMSO was used as
4.2.3. 6-Amino-3-butyl-5-cyclopentanecarboxamido-2,4-
dioxo-1,2,3,4-tetrahydropyrimidine (2c). Yield: 0.91 g
1
(62%). Mp 2878C. H NMR (500 MHz): d¼0.88 (t, 3H,
J¼7.3 Hz, C40H3), 1.25 (sext, 2H, J¼7.3 Hz, C30H2), 1.46
(quint, 2H, J¼7.3 Hz, C20H2), 1.49–1.82 (m, 8H, cyclo-
pentyl-CH2), 2.74 (quint, 1H, J¼7.8 Hz, C100H), 3.67 (t, 2H,
J¼7.2 Hz, C10H2), 5.80 (s, 2H, NH2), 8.25 (s, 1H, NHCO),
10.37 (br, 1H, N1H). 13C NMR (1205 MHz): d¼00 13.7 (C40),
19.6 (C30), 25.700(C300, C400), 29.8 (C2 ), 30.0 (C2 , C500), 39.1
(C10), 44.0 (C1 ), 87.6 (C5), 149.9, 149.8 (C2, C6), 160.6
(C4), 175.9 (CvO). MS: m/z¼294.2 (Mþ, 25), 276.2
([M2H2O]þ, 4), 198.1 (100), 181.1 (18), 142.0 (46), 97.0
(22), 69.1 (86). Calcd for C14H22N4O3: %C, 57.13; %H,
7.53; %N, 19.03. Found: %C, 57.62; %H, 7.21; %N, 19.38.
1
solvent and internal standard with the chemical shifts H:
2.49 ppm; 13C: 39.7 ppm. All chemical shifts were expressed
in ppm according to the internal standard. Coupling
constants (J) are given in Hertz (Hz). The assignment of
the carbon and hydrogen atoms was carried out by the
interpretation of 2D-spectra and in comparison with data of
0
similar structures. Atoms 0o0 f residue R1 were quoted with ,
000
atoms of residue R8 with and of R3 with . The reactions
were monitored by thin layer chromatography (TLC) using
aluminium sheets with silica gel 60 F254 (Merck). The
melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. Elemental analyses
were performed by the Institute of Pharmaceutical Chem-
istry Endenich, University of Bonn. The mass spectra were
collected on an MS-50 A.E.I. (Manchester) mass spec-
trometer with an ionisation energy of 70 eV.
4.3. General procedure for the preparation of
compounds 2d and 2e
To a suspension of compound 1a or 1b (4.0 mmol) in
methanol (30 mL) 3-noradamantanecarboxylic acid (0.5 g,
3.0 mmol) and EDC (0.6 g, 3.1 mmol) were added. A clear
yellow solution was obtained, from which a light yellow
product precipitated after stirring at room temperature for
12 h. The precipitate was collected by suction filtration and
washed with methanol (10 mL) and subsequently with water
(15 mL). The collected precipitate was proven to be pure
product.
Compounds 1a and 1b were prepared from 6-aminouracil
(Fluka) via regioselective alkylation followed by nitrosation
and reduction as described.14 Compound 2b15 and 7a17 were
synthesised as described in the literature. Compounds 4b
and 6b were prepared with the presented new methods; they
gave the same analytical results as described in the
literature.11,15 All solvents were purified and dried before
use.
4.3.1. 6-Amino-5-(hexahydro-2,5-methanopentalene-
3a)-carboxamido-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-
pyrimidine (2d). Yield: 0.91 g (66%). Mp 2958C. 1H NMR
(500 MHz): d¼0.81 (t, 3H, J¼7.4 Hz, C30H3), 1.41–1.64
(m, 6H, C20H2, C100HH, C600HH, C700H2), 1.80 (m, 4H,
4.2. General procedure for the preparation of
compounds 2a–c
To a stirred suspension of compound 1a or 1b (5.0 mmol) in
methanol (30 mL) first cyclopentane carboxylic acid (0.6 g,
0.55 mL, 5.3 mmol), or benzoic acid (0.65 mg, 5.3 mmol),
then N0-(3-dimethylaminopropyl)-N-ethylcarbodiimide
hydrochloride (EDC) (1.0 g, 5.2 mmol) was added. The
reaction mixture was stirred at room temperature for 3 h.
The precipitate was collected by suction filtration and
washed with methanol (15 mL) and subsequently with H2O
(15 mL). For analytical purposes, the product was recrys-
tallised from methanol/water.
00
C1 HH, C300HH, C400HH, C600HH), 2.01 (m, 2H, C300HH,
00
C4 HH), 2.23 (m, 2H, C2000H, C500H), 2.68 (m, 1H, C6a00H),
3.62 (t, 2H, J¼7.4 Hz, C1 H2), 5.75 (s, 2H, NH2), 7.71 (s,
1H, NHCO), 9.85 (br, 01H, N1H).0013C NMR (125 MHz):
d¼11.1 (C30), 20.9 (C2 ), 34.4 (C7 ), 36.9 (2H, C200, C500),
39.8 (C10), 42.3 (C6a00), 43.1 (2C, C100, C600), 46.8 (2C, C300,
C400), 54.6 (C3a00), 87.7 (C5), 149.6 (2H, C2, C6), 160.2
(C4), 176.3 (CvO). MS: m/z (%): 332.2 (Mþ, 3.5), 184.1
(66), 142.1 (100), 121.1 (14). Calcd for C17H24N4O3: %C,
62.41; %H, 7.56; %N, 16.17. Found: %C, 62.22; %H, 7.53;
%N, 15.86.
4.2.1. 6-Amino-5-benzamido-3-butyl-2,4-dioxo-1,2,3,4-
tetrahydropyrimidine (2a). Yield: 1.07 g (71%). Mp
288–2898C. 1H NMR (500 MHz): d¼0.88 0 (t, 3H,
J¼7.4 Hz, C40H3), 1.26 (sext, 2H, J¼7.4 Hz, C3 H2), 1.47
(quint, 2H, J¼7.4 Hz, C20H2), 3.72 (t, 2H, J¼7.4 Hz,
C10H2), 6.04 (br, 2H, NH2), 7.44–7.52 (m, 3H, aromatic-
CH), 7.94–7.96 (m, 2H, aromatic-CH), 8.84 (s, 1H,
NHCO), 10.44 (s, 1H, 0 N1H). 13C0 NMR (125 MHz):
d¼13.9 (C40), 19.800 (C3 ), 30.0 (C2 ), 39.2 (C10), 87.2
(C5), 128.0 (C300, C5 ), 128.1 (C200, C600), 131.3 (C400), 134.7
(C100), 150.1, 150.6 (C2, C6), 160.5 (C4), 166.5 (CvO).
4.3.2. 6-Amino-3-butyl-5-(hexahydro-2,5-methanopen-
talene-3a)-carboxamido-2,4-dioxo-1,2,3,4-tetrahydro-
pyrimidine (2e). Yield: 0.95 g (69%). Mp 2788C. 1H NMR
(500 MHz): d¼0.87 (t, 3H, J¼7.4 Hz, C40H3), 1.27 (sext,
2H, J¼7.4 Hz, C30H2), 1.41–1.56 (m, 6H, C20H2, C100HH,
C60000HH, C700H2), 1.79 (m, 4H, C100HH, C300HH, C400HH,
C6 HH), 2.01 (m, 2H, C300HH, C400HH), 2.23 (m, 2H, C0200H,
C500H), 2.68 (m, 1H, C6a00H), 3.66 (t, 2H, J¼7.3 Hz, C1 H2),
5.69 (s, 2H, NH2), 7.70 (s, 1H, NHCO), 10.30 (br, 1H,

S. Weyler et al. / Tetrahedron 59 (2003) 47–54
51
N1H). 13C NMR (125 MHz): d¼13.6 (C40), 19.6 (C30), 29.7
4.4.3. 6-Amino-3-butyl-5-(hexahydro-2,5-methanopen-
talene-3a)-carboxamido-1-(3-hydroxypropyl)-2,4-dioxo-
1,2,3,4-tetrahydropyrimidine (3e). When the reaction was
completed (TLC), water (20 mL) and diethyl ether (20 mL)
were added and the mixture was stirred for 4 h. Then it was
stored at 48C until white solid material precipitated, which
was isolated by suction filtration and washed twice with
diethyl ether (10 mL). The obtained pure product required
no further purification.
(C20), 34.4 (C700), 36.9 (2C, C200, C500), 39.000 (C10), 42.3
00
(C6a ), 43.1 (2C, C100, C600), 46.8 (2C, C3 , C400), 54.6
00
(C3a ), 87.7 (C5), 149.5 (2C, C2, C6), 160.2 (C4), 176.3
(CvO). MS: m/z¼346.2 (Mþ, 23), 198.1 (25), 181.1 (13),
149.1 (52), 142.0 (44), 121.1 (100), 97.0 (22). Calcd for
C18H26N4O3: %C, 61.43; %H, 7.28; %N, 16.85. Found: %C,
60.98; %H, 7.31; %N, 16.54.
4.4. General procedure for the 3-hydroxyalkylation in
position 1 of the uracil derivatives
Yield: 0.15 g (19%). Mp 1728C. 1H NMR (300 MHz):
d¼0.87 (t, 3H, J¼7.3 Hz, C40H3), 1.24 (sext, 2H, J¼7.3 Hz,
C30H2), 1.40–1.68 (m, 6H, C20H2, C100HH, C600HH, C700H2),
1.70–1.81 (m, 6H, C100HH, C300HH, C400HH, C600HH,
C200000H2), 2.06 (m, 2H, C300HH, C400HH), 2.23 (m, 2H,
C2 H, C500H), 2.71 (m, 1H, C6a00H), 3.43 (t, 2H, J¼5.6 Hz,
C3000H2), 3.72 (t, 2H, J¼7.3 Hz, C10H2), 3.91 (t, 2H,
J¼6.9 Hz, C1000H2), 4.72 (m, 1H, OH), 6.25 (s, 2H, NH2),
7.72 (s, 1H, NHCO). 13C NMR 00(075 MHz): d¼13.6 (C40),
A solution of compound 2b or 2c (2.0 mmol) in dried
dimethylformamide (DMF) (20 mL) was prepared under an
inert atmosphere of argon. Potassium carbonate (0.4 g,
2.9 mmol) was added. The reaction mixture was stirred at
room temperature for 6 h and then heated to 808C for 1 h.
After cooling to room temperature the undissolved potass-
ium carbonate was removed from the mixture by suction
filtration. The filtrate was heated again to 808C and 3-
bromopropanol (1.4 g, 0.9 mL, 10 mmol) was added. The
reaction mixture was stirred for another 12 h under an argon
atmosphere at 808C. As soon as nearly all starting material
had disappeared (TLC: dichloromethane/methanol/ammo-
nia (25%)¼180:20:1) the solvent was removed by distilla-
tion under reduced pressure. The residue was suspended in a
mixture of methanol and water (1:1) and the solid material,
which was identified as starting material, was filtered off.
The methanol was removed under reduced pressure and
diethyl ether (20 mL) was added. The mixture was stirred
for 3 h. Then it was stored at 48C until a white pure
precipitate was formed, which was isolated by suction
filtration and washed twice with cold diethyl ether (20 mL).
The products were used without further purification for the
next step.
00
19.6 (C30), 29.7 (C20), 30.7 (C2 ), 34.4 (C7 ), 37.0 (2H,
00
00
00
C2 , C5 ), 39.8 (C10), 40.0 (C1000), 42.2 (C6a ), 43.1 (2H,
00
00
C1 , C6 ), 46.7 (2C, C300, C400), 54.7 (C3a00), 57.7 (C3000),
88.5 (C5), 151.3, 150.0 (2H, C2, C6), 158.7 (C4), 176.7
(CvO). MS: m/z (%): 404.3 (Mþ, 38), 386.3 (12.5), 255.1
(33.5), 238.1 (14), 149.1 (36), 121.1 (100). HRMS: calcd:
404.2425. Found: 404.2429.
4.5. General procedure for the ring closure to obtain
1,3,8-trisubstituted xanthines
Method A. Compound 3b or 3c (0.3 mmol) was stirred in a
mixture of methanol (10 mL) and aqueous NaOH (10%,
2.0 mL) at 608C for 24 h. Then water (10 mL) was added
and the solution was acidified with concentrated HCl to pH
2–3. The methanol was distilled off under reduced pressure
and the aqueous solution was stored at 48C for 24 h. A white
flaky material precipitated, which was isolated by suction
filtration and washed with ice-cold water.
4.4.1. 6-Amino-5-cyclopentanecarboxamido-1-(3-hydro-
xypropyl)-2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrimi-
dine (3b). Yield: 0.17 g (25%). Mp 1618C. 1H NMR
(300 MHz): d¼0.81 (t, 3H, J¼7.5 Hz, C30H3), 1.45–1.83
(m, 12H, C20H2, C200H2, cyclopentyl-CH2), 2.75 (quint, 1H,
J¼7.9, C100H), 3.43 (t, 2H, J¼5.6 Hz, C3000H2), 3.69 (t, 2H,
J¼7.3 Hz, C10H2), 3.87 (t, 2H, J¼7.0 Hz, C1000H2), 4.69 (br,
1H, OH), 6.34 (s, 2H, NH2), 8.16 (s, 1H, NHCO). 13C NMR
(75 MHz): d¼0011.100(C30), 20.8 (C20), 25.7 (2C, C300, C4000),
29.8 (2C0,0 C2 , C5 ), 30.7 (C2000), 39.8 (C1000), 41.8 (C1 ),
44.0 (C1 ), 57.8 (C3000), 88.1 (C5), 151.3, 150.1 (C2, C6),
158.8 (C4), 175.8 (CvO).
Method B. Compound 3b or 3c (0.4 mmol) was stirred in
1,1,1,3,3,3-hexamethyldisilazane (HMDS) (10 mL) in the
presence of a catalytic amount of ammonium sulphate (ca.
20 mg) under reflux for 48 h. HMDS was removed by
distillation under reduced pressure. The oily residue was
suspended in water (10 mL) and acidified with concentrated
HCl to pH 2–3. The aqueous solution was stored at 48C
until white material precipitated, which was isolated by
suction filtration and washed with ice-cold water.
4.4.2. 6-Amino-3-butyl-5-cyclopentanecarboxamido-1-
(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
dine (3c). Yield: 0.24 g (34%). Mp 1458C. 1H NMR
(300 MHz): d¼0.86 (t, 3H, J¼7.3, C40H3), 1.24 (sext, 2H,
J¼7.3, C30H2), 1.40–1.83 (m, 12H, C20H2, C2000H2, cyclo-
pentyl-CH2), 2.74 (quint, 1H, J¼7.8 Hz, C100H), 3.43 (t, 2H,
J¼6.1 Hz, C3000H2), 3.72(t, 2H, J¼7.3 Hz, C10H2), 3.89(t, 2H,
J¼7.0 Hz, C1000H2), 4.69 (br, 1H, OH), 6.34 (s, 2H, NH2), 8.15
(s, 1H, NHCO). 13C NMR (75 MHz): d¼14.0 (C40), 20.0
(C30), 26.1 (2C, C300,00C0 400), 30.1 (C20), 30.3 (020 C, C200, C500),
30.9 (C2000), 39.5 (C1 ), 40.7 (C10), 44.6 (C1 ), 58.300(C3000),
88.5(C5), 152.0,150.6 (C2, C6), 159.5 (C4), 177.1(C1 ). MS:
m/z¼353.2 (Mþ, 49), 334.2 (21), 256.1 (100), 238.1 (24), 97.1
(11), 69.1 (58). HRMS: calcd 352.2111. Found: 352.2110.
The products were recrystallized from DMSO by the
dropwise addition of water.
4.5.1. 8-Cyclopentyl-3-(3-hydroxypropyl)-1-propyl-3,7-
dihydropurine-2,6-dione (4b). Yield: 31 mg (32%,
method A), 56 mg (44%, method B), lit.19 yield: 75%.
Mp 1988C, lit.19 mp 207–2088C. 1H NMR was identical to
0
19 13
literature data.
C NMR (75 MHz): 0d00 ¼11.0 (C3 ), 20.7
(C20), 25.0 (2C, C3 , C400), 31.0 (C2 ), 31.8 (2C, C200,
C500), 38.6 (C100), 40.4 (C1000), 41.9 (C10), 58.3 (C3000), 105.9
(C5), 147.4 (C8), 150.4 (C4), 153.5 (C2), 157.5 (C6). MS:
m/z (%): 320.2 (Mþ; 60), 303.1 (15), 262.1 (34), 234.1
(100), 194 (35), 179.1 (24), 69.1 (24). HRMS: calcd:
320.1848. Found: 320.1847. Calcd for C17H26N4O3: %C,
00

52
S. Weyler et al. / Tetrahedron 59 (2003) 47–54
59.98; %H, 7.55; %N, 17.49. Found: %C, 59.23; %H, 7.51;
%N, 17.11.
pressure. The products were isolated by gradient column
chromatography (dichloromethane/methanol¼100:1 to
100:10).
4.5.2. 1-Butyl-8-cyclopentyl-3-(3-hydroxypropyl)-3,7-
dihydropurine-2,6-dione (4c). Yield: 35 mg (35%, method
A), 41 mg (31%, method B). Mp 18038C. 1H NMR
(300 MHz): d¼0.84 (t, 3H, J¼7.3 Hz, C3 H3), 1.27 (sext,
2H, J¼7.4 Hz, C30H2), 1.45–2.03 (m, 12H, C20H2, C2000H2,
cyclopentyl-CH2), 3.13 (quint, 1H, J¼8.0 Hz, C100H), 3.42
(t, 2H, J¼6.3 Hz, C3000H2), 3.86 (t, 2H, J¼7.3 Hz, C10H2),
4.02 (t, 2H, J¼7.1 Hz, C1000H2), 4.48 (br, 1H, OH), 13.08 (br,
1H, N7H). 13C NMR (75 MHz): d¼13.300(0C40), 19.3 (C300)0,
24.7 (2C, C300,00C400), 29.3 (C20), 30.7 (C2 ), 31.5 (2C, C2 ,
C500), 38.4 (C1 ), 39.8 (C1000), 40.1 (C10), 58.0 (C3000), 105.7
(C5), 147.1 (C8), 150.1 (C4), 153.2 (C2), 157.2 (C6). MS:
m/z (%): 320.2 (Mþ, 60), 303.1 (15), 262.1 (34), 234.1
(100), 194 (35), 179.1 (24), 69.1 (24). HRMS: calcd:
4.6.1. 9-Benzamido-7-butyl-6,8-dioxo-1,3,4,6,7,8-hexa-
hydro-2H-pyrimido[1,6-a]pyrimidine (5a). Yield: 0.37 g
1
(57%). Mp 179–1808C. H NMR (500 MHz): d¼0.88 (t,
3H, J¼7.4 Hz, C40H3), 1.26 (sext, 2H, J¼7.4 Hz, C30H2),
1.47 (quint, 2H, J¼7.4 Hz, C20H2), 1.91 (quint, 2H,
J¼5.8 Hz, C3H2), 3.21 (m, 2H, C4H2), 3.74 (t, 2H,
J¼7.4 Hz, C10H2), 3.81 (t, 2H, J¼5.8 Hz, C2H2), 7.21 (br,
1H, N1H), 7.45–7.54 (m, 3H, aromatic-CH), 7.96–7.98 (m,
2H, aromatic-CH), 8.81 (s, 1H, NHCO). 13C NMR
(125 MHz): d¼13.9 (C40), 19.8 (C30), 20.2 (C3), 30.0
(C20), 38.4 (C4), 40.0 (C100)0 , 40.8 (C2), 86.2 (C9), 128.1 (20C0 ,
C300, C500), 128.1 (2C, C2 , C600), 131.3 (C400), 134.7 (C1 ),
149.5 (C6), 150.2 (C9a), 158.8 (C8), 166.8 (CvO). MS:
m/z¼342.2 (Mþ, 46), 237.2 (100), 181.1 (13), 110 (8), 105.1
(18). HRMS: calcd: 342.1692. Found: 342.1693.
334.2005.
Found:
334.2006.
Calcd
for
C17H26N4O3·0.5H2O: %C, 59.46; %H, 7.92; %N, 16.31.
Found: %C, 59.71; %H, 7.81; %N, 16.28.
4.6.2. 9-Cyclopentanecarboxamido-6,8-dioxo-7-propyl-
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,6-a]pyrimidine
(5b). Yield: 0.36 g (56%). Mp 1798C. 1H NMR (500 MHz):
d¼0.82 (t, 3H, J¼7.0 Hz, C30H3), 1.45–1.93 (m, 12H,
C20H2, C3H2, cyclopentyl-CH2), 2.73 (quint, 1H, J¼7.9 Hz,
C100H2), 3.21 (m, 2H, C2H2), 3.68 (t, 2H, J¼7.4 Hz, C10H2),
3.77 (t, 2H, J¼6.4 Hz, C4H2), 6.81 (s, 1H, N1H), 8.05 (s,
1H, NHCO). 13C NMR (125 MHz): d¼11.1 (C30), 200.00 (C3),
20.8 (C20), 25.6 (2C, C300,0 C400), 29.8 (2C, C200, C5 ), 38.2
(C2), 40.5 (C4), 41.5 (C1 ), 44.0 (C100), 86.3 (C9), 149.8,
148.9 (C6, C9a), 158.3 (C8), 176.0 (CvO). MS: m/z¼320.2
(Mþ, 26), 302.1 (5), 223.1 (100), 181.0 (28), 149.0 (17),
69.1 (26). HRMS: calcd: 320.1848. Found: 320.1850.
4.5.3. 1-Butyl-8-(hexahydro-2,5-methanopentalen-3a-
yl)-3-(3-hydroxypropyl)-3,7-dihydropurine-2,6-dione
(4e). Compound 3e (0.2 g, 0.5 mmol) was stirred in HMDS
(20 mL) in the presence of a catalytic amount of ammonium
sulphate (ca. 20 mg) under reflux for 18 h. Then water
(10 mL) was added and the reaction mixture was neutralized
with concentrated HCl. The light yellow precipitate was
isolated by suction filtration, washed with ice-cold water
and
purified
by
column
chromatography
(dichloromethane/methanol¼98:2).
Yield: 64 mg (33%). Mp 1828C. 1H NMR (500 MHz):
d¼0.88 (t, 3H, J¼7.4 Hz, C40H3), 1.27 (sext, 2H, J¼7.6 Hz,
C30H2), 1.51 (quint, 2H, J¼7.4 Hz, C20H2), 1.61 (m, 4H,
C100HH, C600HH, C700H2), 1.80 (quint, 2H, J¼6.8 Hz,
C2000H2), 1.91 (m, 4H, C100HH, C300HH, C400HH, C600HH),
2.12 (m, 2H, C300HH, C400HH), 2.29 (m, 2H, C200H, C500H),
2.60 (t, 1H, J¼6.8 Hz, C6a00H), 3.41 0(q, 2H, J¼6.0 Hz,
C3000H2), 3.87 (t, 2H, J¼7.4 Hz, C1 H2), 4.02 (t, 2H,
J¼6.9 Hz, C1000H2), 4.52 (t, 1H, J¼5.5 Hz, OH), 13.02 (s,
1H, N7H). 13C NMR0(00125 MHz): d¼13.8 (C40), 19.7 (C30),
4.6.3. 7-Butyl-9-cyclopentanecarboxamido-6,8-dioxo-
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,6-a]pyrimidine
(5c). Yield: 0.42 g (63%). Mp 1868C. 1H NMR (500 MHz):
d¼0.82 (t, 3H, J¼7.3 Hz, C40H3), 1.25 (sext, 2H, J¼7.4 Hz,
C30H2), 1.40–1.91 (m, 12H, C20H2, C3H2, cyclopentyl-CH2),
2.74(quint, 1H, J¼7.9 Hz, C100H), 3.21 (m, 2H, C2H2),3.72(t,
2H, J¼7.3 Hz, C10H2), 3.78 (t, 2H, J¼5.8 Hz, C4H2), 6.81 (s,
1H, N1H), 0 8.05 (s, 1H, NHCO). 13C NMR (12500MHz):
d¼11.1 (C4 )0,0 19.600(C30), 20.0 (C3), 25.6 (2C, C300, C4 ), 29.8
(3C0,0 C20, C2 , C5 ), 38.2 (C2), 39.7 (C4), 40.5 (C10), 44.0
(C1 ), 86.3 (C9), 149.7, 148.9 (C6, C9a), 158.3 (C8), 176.0
(CvO). MS: m/z¼334.3 (Mþ, 44), 318.2 (5), 237.2 (100),
181.1 (36), 69.1 (23). HRMS: calcd: 334.2005. Found:
334.2014. Calcd for C17H26N4O3: %C, 61.06; %H, 7.84;
%N, 16.75. Found: %C, 60.45; %H, 7.80; %N, 16.25.
00
00
29.8 (C20), 31.2 (C2 ), 34.3 (C7 ), 37.1 (2C, C2 , C500),
40.3, 400.05 (C10, C1000), 43.300(2C, C1 , C600), 45.3 (C6a ), 48.4
(2C, C3 , C400), 49.0 (C3a ), 58.5 (C3000), 106.8 (C5), 147.7
(C8), 150.8 (C4), 154.0 (C2), 160.1 (C6). MS: m/z (%): 386.2
(Mþ, 100), 369.2 (49), 286.2 (68). HRMS: calcd: 386.2318.
Found: 386.2309. Calcd for C21H30N4O3: %C, 65.26; %H,
7.82; %N, 14.50. Found: %C, 64.99; %H, 7.83; %N, 14.40.
00
00
4.6. General procedure for the preparation of 7,9-
disubstituted 1,3,4,6,7,8-hexahydro-2H-pyrimido-
[1,6-a]pyrimidine-6,8-diones
4.6.4. 9-(Hexahydro-2,5-methanopentalene-3a)-carboxa-
mido-6,8-dioxo-7-propyl-1,3,4,6,7,8-hexahydro-2H-pyri-
mido[1,6-a]pyrimidine (5d). Yield: 0.31 g (42%). Mp
1948C. 1H NMR (500 MHz)0: d¼0.87 (t, 3H, J¼7.3 Hz,
C30H3), 1.50–1.61 (m, 6H, C2 H2, C100HH, C600HH, C700H2),
1.80 (m, 4H, C100HH, C300HH, C400HH, C600HH), 1.91 (m,
2H, C3H2), 2.08 (m, 2H, C300HH, C400HH), 2.24 (m, 2H,
C200H, C500H), 2.72 (t, 1H, J¼6.7 Hz, C6a00H), 3.24 (m, 2H,
C4H2), 3.67 (t, 2H, J¼7.4 Hz, C10H2), 3.79 (t, 2H,
J¼5.8 Hz, C2H2), 6.66 (s, 1H, N1H), 7.61 (s, 1H,
NHCO). 13C NMR00(125 MHz): d¼11.200(C30), 20.8 (C20),
20.8 (C3), 34.5 (C7 ), 36.9 (2C, C200, C5 ), 38.040 (C4), 40.6
(C10), 41.6 (C2), 42.2 (C6a00), 43.1 (2C, C100, C6 ), 46.8 (2C,
A solution of compound 2a, 2b, 2c, 2d or 2e (2.0 mmol) in
dried dimethylformamide (DMF) (20 mL) was prepared in
an inert atmosphere of argon. Potassium carbonate (0.5 g,
3.6 mmol) was added. The solution was heated at 608C for
1 h. Then 1,3-dibromopropane (1.98 g, 1.3 mL, 10 mmol)
was added. The reaction mixture was stirred for another 2 h
under an argon atmosphere. As soon as all starting material
had disappeared (TLC: dichloromethane/methanol¼9:1),
the solvent was removed by distillation under reduced

S. Weyler et al. / Tetrahedron 59 (2003) 47–54
53
C300, C400), 54.7 (C3a00), 86.6 (C9), 149.8, 149.0 (C6, C9a),
4.7. General procedure for the preparation of 4,5-
dihydro-6H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-
diones
158.2 (C8), 176.9 (CvO). MS: m/z¼372.2 (Mþ, 43), 223.1
(100), 181.0 (24), 149.1 (41), 121.1 (88). HRMS: calcd:
372.2161. Found: 372.2153.
Compound 5a, 5b, 5c, 5d or 5e (1.0 mmol) was stirred in
HMDS (30 mL) for 18 h under reflux. Then HMDS was
removed by distillation under reduced pressure. The product
4.6.5. 7-Butyl-9-(hexahydro-2,5-methanopentalene-3a)-
carboxamido-6,8-dioxo-1,3,4,6,7,8-hexahydro-2H-pyri-
mido[1,6-a]pyrimidine (5e). Yield: 0.40 g (53%). Mp
1998C. 1H NMR (500 MHz): d¼0.87 (t, 3H, J¼7.3 Hz,
C40H3), 1.25 (sext, 2H, J¼7.3 Hz, C30H2), 1.40–1.61 (m,
6H, C20H2, C100HH, C600HH, C700H2), 1.80 (m, 4H, C100HH,
C300HH, C400HH, C600HH), 1.91 (m, 2H, C3H2), 2.01 (m, 2H,
C300HH, C400HH), 2.24 (m, 2H, C200H, C500H), 2.73 (t, 1H,
J¼6.7 Hz, C6a00H), 3.24 (m, 2H, C4H2), 3.72 (t, 2H,
J¼7.3 Hz, C10H2), 3.78 (t, 2H, J¼5.9 Hz, C2H2), 6.65 (s,
1H, N1H), 7.60 (s, 1H, NHCO). 13C NMR (125 MHz):
d¼13.6 (C40)0,0 19.6 (C30), 20.1 (C3), 29.80(C20), 34.5 (C700),
37.0 0(02H, C2 , C500), 38.4 (C4), 39.8 (C1 ), 40.6 (C2), 42.2
(C6a00), 43.2 (2C, C100, C600), 46.8 (2C, C300, C400), 54.7
(C3a ), 86.7 (C9), 149.1, 150.0 (C6, C9a), 158.4 (C8), 177.1
(CvO). MS: m/z¼386.3 (Mþ, 47.5), 237.1 (100), 181.0
(31), 149.1 (46), 121.1 (100). HRMS: calcd: 386.2318.
Found: 386.2311. Calcd for C21H30N4O3: %C, 65.26; %H,
7.82; %N, 14.50. Found: %C, 65.55; %H, 7.79; %N, 14.05.
was
purified
by
column
chromatography
(dichloromethane/methanol¼100:2).
4.7.1. 9-Butyl-2-phenyl-4,5-dihydro-6H,8H-pyri-
mido[1,2,3-cd]purine-8,10(9H)-dione (6a). Yield: 0.21 g
(64%). Mp 210–2118C.
Alternatively compound 6a was prepared by the following
procedure. Compound 8a (0.2 g, 0.6 mmol) was dissolved
in SOCl2 (20 mL) and then refluxed for 1 h. After cooling to
room temperature, the reaction mixture was stirred over-
night. SOCl2 was removed under reduced pressure and
subsequently ice-cold water (30 mL) was added. The
precipitate was isolated by suction filtration and purified
by recrystallisation from DMF followed by dropwise
addition of water.
Yield: 0.17 g (87%). Mp 210–2118C. 1H NMR (500 MHz):
d¼0.90 (t, 3H, J¼7.4 Hz, C40H3), 1.30 (sext, 2H, J¼7.4 Hz,
C30H2), 1.52 (quint, 2H, J¼7.4 Hz, C20H2), 2.20 (quint, 2H,
J¼5.8 Hz, C5H2), 3.86–3.89 (m, 4H, C10H2, C4H2), 4.26 (t,
3H, J¼5.8 Hz, C6H2), 7.49–7.54 (m, 3H, aromatic-CH),
7.76–7.78 (m, 2H, aromatic-CH). 13C NMR (125 MHz):
d¼13.9 (C40), 19.8 (C30), 21.1 (C5), 29.9 (C20), 38.8 (C6),
40.3 (C10), 42.9 (C4), 113.7 (C11), 127.8 (C300, C500), 129.0
(C200, C600), 129.5 (C400), 139.5 (C12), 145.1 (C2), 149.7
(C8), 156.8 (C10). MS: m/z (%)¼324.2 (Mþ; 100), 307.2
(86), 282.2 (14), 268.1 (28), 225 (100), 197.1 (8), 145.2
(38), 117 (22). HRMS: calcd: 324.1586. Found: 324.1585.
Calcd for C18H20N4O2·0.5H2O: %C, 64.85; %H, 6.35; %N,
16.81. Found: %C, 64.78; %H, 6.12; %N, 16.66.
4.6.6. 6-Butyl-8-cyclopentanecarboxamido-5,7-dioxo-
1,2,3,5,6,7-hexahydroimidazo[1,2-c]pyrimidine
Compound 9c was prepared from compound 2c in analogy
to the method described for compounds 5a–e, but instead of
1,3-dibromopropane 1,2-dibromoethane (1.9 g, 1.3 mL,
10 mmol) was used.
(9c).
Yield: 0.22 g (34%). Mp 1458C. 1H NMR (300 MHz):
d¼0.87 (t, 3H, J¼7.3 Hz, C40H3), 1.24 (sext, 2H, J¼7.4 Hz,
C30H2), 1.40–1.80 (m, 10H, C20H2, cyclopentyl-CH2), 2.73
(quint, 1H, J¼7.9 Hz, C100H), 3.58 (t, 2H, J¼8.5 Hz, C3H2),
3.69 (t, 2H, J¼7.3 Hz, C10H2), 3.97 (t, 2H, J¼8.6 Hz,
C2H2), 7.15 (s, 1H, N1H), 8.38 (s, 1H, NHCO). 13C NMR
(75 MHz): d¼13.6 (C40), 19.5 (C30), 25.7 (2C, C300, C400),
29.9 (C20), 29.9 (2C, C200, C500), 39.4 (C10), 41.8 (C3), 43.8
(C100), 44.0 (C2), 85.6 (C8), 148.2, 151.2 (C5, C8a), 160.6
(C7), 175.0 (CvO). MS: m/z¼320.2 (Mþ, 29), 302.1 (4),
224.1 (73), 167.0 (37), 149.0 (100), 96.0 (25), 69.1 (38).
HRMS: calcd: 320.1848. Found: 320.1839.
4.7.2. 2-Cyclopentyl-9-propyl-4,5-dihydro-6H,8H-pyri-
mido[1,2,3-cd]purine-8,10(9H)-dione (6b). Yield: 0.11 g
1
(38%). Mp 1688C. H NMR and 13C NMR are identical to
literature data.11
4.7.3. 9-Butyl-2-cyclopentyl-4,5-dihydro-6H,8H-pyri-
mido[1,2,3-cd]purine-8,10(9H)-dione (6c). Yield: 0.19 g
4.6.7. 8-Butyl-10-cyclopentanecarboxamido-7,9-dioxo-
1,2,3,4,5,7,8,9-octahydropyrimido[1,6-a][1,3]diazepine
(10c). Compound 10c was prepared from compound 2c
(1.7 mmol) in analogy to the method described for
compounds 5a–e, but instead of 1,3-dibromopropane 1,4-
dibromobutane (1.9 g, 1.0 mL, 8.5 mmol) was used.
1
(60%). Mp 1558C. H NMR (500 MHz): d¼0.87 (t, 3H,
J¼7.4 Hz, C40H3), 1.26 (sext, 2H, J¼7.4 Hz, C30H2), 1.47
(quint, 2H, J¼7.4 Hz, C20H2), 1.50–2.00 (m, 8H, cyclo-
pentyl-CH2), 2.18 (quint, 2H, J¼5.7 Hz, C5H2), 3.19 (quint,
1H, J¼7.9 Hz, 100H), 3.81 (t, 2H, J¼5.8 Hz, C4H2), 3.82 (t,
2H, J¼7.5 Hz, C10H2), 4.01 (t, 2H, J¼5.8 Hz, C6H2). 13C
NMR (125 MHz): d¼13.9 (C40), 19.8 (C30), 20.8 (C5), 25.3
(2C, C300, C400), 30.0 (C20), 30.8 (2C, C200, C500), 36.1 (C100),
38.9 (C6), 40.1 (C4), 40.1 (C10), 111.8 (C11), 138.9 (C12),
149.8 (C2), 150.5 (C8), 156.7 (C10). MS: m/z (%)¼316.1
(Mþ, 58), 299.2 (95), 275 (86), 260 (32), 217 (100). HRMS:
calcd: 316.1899. Found: 316.1902.
1
Yield: 0.16 g (28%). Mp 225–2308C (decomposition). H
NMR (500 MHz): d¼0.87 (t, 3H, J¼7.3 Hz, C40H3), 1.24
(sext, 2H, J¼7.4 Hz, C30H2), 1.45 (quint, 2H, J¼7.3 Hz,
C20H2), 1.48–1.83 (m, 12H, C3H2, C4H2, cyclopentyl-
CH2), 2.75 (quint, 1H, J¼8.0 Hz, C100H), 3.19 (m, 2H,
C5H2), 3.73 (t, 2H, J¼7.5 Hz, C10H2), 4.00 (m, 2H, C2H2),
5.76 (s, 1H, N1H), 8.34 (s, 1H0, NHCO). 13C NMR
(125 MHz): d¼13.8 (C40), 19.8 (C3 ), 25.8 (C3), 25.9 (2C,
C300, C400), 26.3 (C4), 29.7 (C20), 30.0 (2C, C200, C500), 39.4
(C10), 44.2 (C100), 45.7 (C5), 45.9 (C2), 93.39 (C10), 151.1,
155.3, 159.5 (C7, C9, C10a), 175.0 (CvO).
4.7.4. 2-(Hexahydro-2,5-methanopentalen-3a-yl)-4,5-
dihydro-9-propyl-6H,8H-pyrimido[1,2,3-cd]purine-8,10
(9H)-dione (6d). Yield: 0.22 g (60%). Mp 1828C. 1H NMR
(500 MHz): d¼0.84 (t, 3H, J¼7.4 Hz, C30H3), 1.51 (sext,

54
S. Weyler et al. / Tetrahedron 59 (2003) 47–54
2H, J¼7.4 Hz, C20H2), 1.62 (m, 2H, C700H2), 1.68 (dd, 2H,
J¼11.3 Hz,00 J¼2.1 Hz (W-couplin0g0 to C300HH, C400HH),
C100HH, C6 HH), 1.87 (m, 2H, C1 HH, C600HH), 1.94 (m,
2H, C300HH, C400HH), 020 .10 (dd, 2H, J¼010 0.7, 2.2 Hz (W-
coupling to C100HH, C6 HH), C300HH, C040 HH), 2.19 (quint,
2H, J¼5.7 Hz, C5H2), 2.31 (m, 2H, C2 H, C500H), 2.82 (t,
1H, J¼6.7 Hz, C6a00H), 3.79, 3.80 (m, 4H, C6H2, C10H2),
4.10 (t, 2H, J¼5.7 Hz, C4H2). 13C NMR 00(125 MHz):
d¼11.3 (C30), 21.0 (C20), 21.1 (C5), 34.5 (C7 ), 36.9 (2C,
C200, C500), 38.7 (C6), 41.8 (C4), 41.9 (C10), 42.7 (C6a00),
43.4 (2C, C100, C600), 47.9 (2C, C300, C400), 48.7 (C3a00), 111.5
(C11), 139.5 (C12), 149.8 (C2, or C6), 151.5 (C8), 156.7
(C2 or C6). MS: m/z (%)¼354.3 (Mþ, 100), 312 (21), 269
(43). HRMS: calcd: 354.2056. Found: 354.2054.
J¼5.8 Hz, C3H2), 3.21 (m, 2H, C4H2), 3.76 (t, 2H,
J¼7.4 Hz, C10H2), 3.81 (t, 2H, J¼5.8 Hz, C2H2), 7.21 (br,
1H, N1H), 7.46–7.54 (m, 3H, aromatic-CH), 7.96–7.98 (m,
2H, aromatic-CH), 8.82 (s, 1H, NvCH). 13C NMR
(125 MHz): d¼13.9 (C40), 19.8 (C30), 20.2 (C3), 30.0
(C20), 38.7 (C4), 39.6 (C100)0 , 40.8 (C2), 97.8 (C9), 127.3 (20C0 ,
C300, C500), 128.5 (2C, C2 , C600), 129.0 (C400), 140.0 (C1 ),
148.7 (CHvN), 149.4 (C6), 150.5 (C9a), 156.6 (C8). MS:
m/z (%)¼326.2 (Mþ, 100), 249.2 (17), 181.2 (9), 167.1 (18).
HRMS: calcd 326.1743. Found: 326.1743. Calcd for
C18H22N4O2·0.5H2O: %C, 64.46; %H, 6.91; %N, 16.70.
Found: %C, 64.80; %H, 6.77; %N, 16.81.
4.7.5. 9-Butyl-2-(hexahydro-2,5-methanopentalen-3a-
yl)-4,5-dihydro-6H,8H-pyrimido[1,2,3-cd]purine-
8,10(9H)-dione (6e). Yield: 0.24 g (63%). Mp 1768C. H
References
1
¨
1. Roth, H. J.; Fenner, H. Struktur-Bioreaktivitat-Wirkungs-
bezogene Eigenschaften; Deutscher Apotheker: Stuttgart,
2000.
NMR (500 MHz): d¼0.88 (t, 3H, J¼7.4 Hz, C40H3), 1.27
(sext, 2H, J¼7.5 Hz, C30H2), 1.47 (quint, 2H, J¼7.4 Hz,
C20H2), 1.64 (m, 2H, C700H2), 1.68 (dd, 2H, J¼11.1, 2.2 Hz
(W-coupling to C300HH, C400HH), C100HH, C600HH), 1.87
(m, 2H, C100HH, C600HH), 1.94 (dd, 2H, J¼10.9, 2.1 Hz (W-
coupling to C100HH, C600HH), C300HH, C400HH), 2.10 (m,
2H, C300HH, C400HH), 2.19 (quint, 2H, J¼5.7 Hz, C5H2),
2.32 (m, 2H, C200H, C500H), 2.82 (t, 1H, J¼6.6 Hz, C6a00H),
3.79 (t, 2H, J¼5.8 Hz, C6H2), 3.84 (t, 2H, J¼7.4 Hz,
C10H2), 4.10 (t, 2H, J¼5.7 Hz, C4H2). 13C NM0R (125 MHz):
d¼13.9 (C40), 19.7 (C30), 21.0 (C5), 30.00(C2 ), 34.5 (C700),
36.9 0(0 2C, C200, C500), 38.8 (C6), 40.1 (C1 ), 41.8 (C4), 42.7
(C6a00), 43.5 (2C, C100, C600), 47.9 (2C, C300, C400), 48.7
(C3a ), 111.5 (C11), 139.5 (C12), 149.8 (C2 or C6), 151.5
(C8), 156.7 (C2 or C6). Calcd for C21H28N4O2: %C, 68.45;
%H, 7.66; %N, 15.20. Found: %C, 68.05; %H, 7.69; %N,
15.04.
2. Mu¨ller, C. E.; Thorand, M.; Qurishi, R.; Diekmann, M.;
Jacobson, K. A.; Padgett, W. L.; Daly, J. W. J. Med. Chem.
2002, 45, 3440.
3. Hess, S.; Mu¨ller, C. E.; Frobenius, W.; Reith, U.; Klotz, K.-N.;
Eger, K. J. Med. Chem. 2000, 43, 4636.
4. Golankiewicz, B.; Ostrowski, T.; Goslinski, T.; Januszczyk,
P.; Zeidler, J.; Baranowski, D.; de Clercq, E. J. Med. Chem.
2001, 44, 4284.
5. Boryski, J.; Golankiewicz, B.; de Clercq, E. J. Med. Chem.
1991, 34, 2380.
6. Lewis, J. W.; Bently, K. W.; Cowan, A. Annu. Rev.
Pharmacol. 1971, 11, 241.
7. Bently, K. W.; Hardy, D. G.; Meek, B. J. Am. Chem. Soc.
1967, 89, 3267–3273.
8. Role of Adenosine and Adenine Nucleotides in the Biological
System; Daly, J. W., Imai, S., Nakazawa, M., Eds.; Elsevier:
Amsterdam, 1991; p 119.
4.7.6. 6-Amino-5-(benzylideneamino)-3-butyl-1H-pyri-
midine-2,4-dione (7a). All analytical data are identical to
the data given in literature.17
ˇ
´
¨
9. Simo, O.; Rybar, A.; Alfoldi, J. Synthesis 1995, 837.
ˇ
10. Simo, O.; Rybar, A.; Alfoldi, J. J. Heterocycl. Chem. 2000, 37,
´
¨
1033.
11. Beauglehole, A. R.; Baker, S. P.; Scammells, P. J. J. Med.
Chem. 2000, 43, 4973.
4.7.7. Preparation of 9-(benzylideneamino)-7-butyl-
1,2,3,4-tetrahydropyrimido[1,6-a]pyrimidine-6,8-dione
(8a). A solution of 5a (2 mmol) in dry dimethylformamide
(DMF) (20 mL) containing potassium carbonate (0.5 g,
3.6 mmol) was prepared under an inert atmosphere of argon.
The solution was heated up to 608C for 1 h after which 1,3-
dibromopropane (1.98 g, 1 mL, 10 mmol) was added. The
reaction mixture was stirred under an inert atmosphere of
argon until all starting material had disappeared (TLC
dichloromethane/methanol¼9:1). The solvent was removed
by distillation under reduced pressure. The product was
12. Daves, Jr. D.; Robins, R. K.; Cheng, C. C. J. Am. Chem. Soc.
1962, 84, 1724.
´
13. Mu¨ller, C. E.; Sandoval-Ramırez, J. Synthesis 1995, 1295.
14. Mu¨ller, C. E. Synthesis 1993, 125.
15. Mu¨ller, C. E.; Shi, D.; Manning, M.; Daly, J. W. J. Med. Chem.
1993, 36, 3341.
16. Sauer, R.; Maurinsh, J.; Reith, U.; Fu¨lle, F.; Klotz, K.-N.;
Mu¨ller, C. E. J. Med. Chem. 2000, 43, 440.
´
17. Hayallah, A. M.; Sandoval-Ramırez, J.; Reith, U.; Schobert,
U.; Preiss, B.; Schumacher, B.; Daly, J. W.; Mu¨ller, C. E.
J. Med. Chem. 2002, 45, 1500.
isolated
by
gradient
column
chromatography
(dichloromethane/methanol¼100:1 to 100:10).
Yield: 0.35 g (54%). Mp 1870–1888C. 1H NMR (500 MHz):
d¼0.87 (t, 3H, J¼7.4 Hz, C4 H3), 1.26 (sext, 2H, J¼7.4 Hz,
C30H2), 1.46 (quint, 2H, J¼7.4 Hz, C20H2), 1.91 (quint, 2H,
18. Senga, K.; Shimizu, K.; Nishigaki, S. Chem. Pharm. Bull.
1977, 33, 227.
19. Scammells, P. J.; Baker, S. P.; Belardinelli, L.; Olsson, R. A.
J. Med. Chem. 1994, 37, 2704.