A general and facile route to new trisubstituted purin-8-ones

Article abstract of DOI:10.1055/s-2005-870001

A facile general route was developed to synthesise new trisubstituted purin-8-one derivatives starting from cheap and readily available 5-bromouracil. These fused planar heterocycles present key hydrogen bond donating/accepting functionalities, making the

Full text of DOI:10.1055/s-2005-870001

PAPER
2227
A General and Facile Route to New Trisubstituted Purin-8-ones
G
eneral and Facil
a
e
R
oute to
t
Ne
w
T
h
risubstituted
e
Purin-8-on
r
es ine Gaulon, Harmen P. Dijkstra, Caroline J. Springer*
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Costwold Road, Sutton, SM2 5NG, UK
Fax +44(208)7224205; E-mail: caroline.springer@icr.ac.uk
Received 7 March 2005
boxylic acid.6e However, these starting materials did not
appear suitable for the construction of trisubstituted com-
pounds like 1, as they lead to purin-8-ones in which R3 =
H or R1, R2 and R3 = H. Therefore, an improved synthetic
route was needed in order to access a wide range of trisub-
stituted purin-8-ones 1. Here, we report a facile and gen-
eral five-step pathway to synthesise compounds of type 1
(Figure 1) starting from cheap and readily available 5-bro-
mouracil.
Abstract: A facile general route was developed to synthesise new
trisubstituted purin-8-one derivatives starting from cheap and readi-
ly available 5-bromouracil. These fused planar heterocycles present
key hydrogen bond donating/accepting functionalities, making
them interesting scaffolds for binding to biological targets.
Key words: purin-8-ones, fused-ring systems, nucleophilic aro-
matic substitution, ring-closure, microwave-assisted synthesis
Purine derivatives constitute an enormous class of com-
pounds, which are well-known as therapeutic agents.
These fused heterocycles show strong binding to various
proteins due to their planar structure and their hydrogen
bond donating/accepting ability.1 Purin-8-one or 8-hy-
droxypurine derivatives for example are reported to pos-
sess a wide range of biological activities. Some of them
have excellent binding affinity to the corticotropin-releas-
ing hormone (CRH) receptor, a key player in anxiety re-
lated disorders.2 Others stimulate the humoral immune
response by binding selectively to B-cells.3 8-Hydroxypu-
rine derivatives were also reported as potent interferon in-
ducing agents in the treatment of hepatitis C virus,4 or as
cyclin-dependent kinases (CDKs) inhibitors by binding to
the ATP pocket of the protein.5
R1
N 7
N
O
N 9
R2
R3HN
N
2
1
R2, R3 = CH3 or Ph
n = 1, 2
R1
=
H (F)
n
;
b
a
c
f
d
e
H (F)
Figure 1
The synthetic pathway is outlined in Scheme 1. First, fol-
lowing the nucleophilic amination procedure reported by
Phillips,7 we synthesised a variety of 5-alkylaminouracils
(2a,d–g, Table 1), starting from 5-bromouracil and the
corresponding alkylamine, in 90–94% yields.
We were interested in the synthesis of purin-8-ones with
the general formula 1 (Figure 1). Only a few examples of
this particular family of purine derivatives are known in
the literature.3a,4b,6 To our knowledge, no trisubstituted de-
rivative (R1, R2 and R3 are different from H) has been re-
ported and only one derivative substituted in the position
N-7 (R1 = n-propyl, R2 = n-butyl, R3 = H) was described
in a study of potential immunostimulatory purine deriva-
tives.3a In contrast, the position N-9 (R2) was found to be
more diversely substituted by either alcohols and diols
(identified as enzymic oxidation intermediates of anti-
herpetic 6-deoxyacyclovir6c and famciclovir6a), a benzyl
functionality4b or ribosyl groups.6b,d
5-Alkylaminouracils 2 were then converted into the corre-
sponding 2,4-dichloropyrimidines 3 using phosphorus ox-
ychloride and Et3N8a as a base (Scheme 1). The reactions,
performed at 120 °C, proceeded in similar yields as re-
ported in the literature,8 ranging from 12% to 33% after
chromatography (3a,d–g, Table 1). The presence of the
secondary amine in position 5 of uracils 2 (Scheme 1) de-
activates the ring toward nucleophilic chlorination and is
responsible for the moderate yields.9 Attempts to optimise
further this dichlorination reaction were performed by
first forming the monosodium salt of the uracil with
NaH10a or NaOH10b followed by reaction with phe-
nylphosphonyldichloride at 160 °C. This procedure, re-
ported in the literature to activate the uracil derivative
towards chlorination,10 led in our case to similar yields as
previously obtained. However, in the case of 2e, we man-
aged to improve the yield from 14% to 23% by using
phenylphosphonyldichloride instead of phosphorus oxy-
chloride and by conducting the reaction at 160 °C instead
of 120 °C.
Two strategies are used in the literature to synthesise these
purin-8-ones. In the first, the modification of guanine
derivatives4b,6b,d involved long synthetic pathways and
gave low yields. The second more general route involved
the construction of the fused heterocyclic skeleton by
modification of the pyrimidine derivatives 2-amino-4,6-
dichloropyrimidine3 and 2,4-diaminopyrimidine-5-car-
SYNTHESIS 2005, No. 13, pp 2227–2233
x
x.
x
x
.
2
0
0
5
Although we were not able to improve the yields for the
chlorination reaction, the cheap and readily available
starting material combined with the straightforward puri-
Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-870001; Art ID: P03305SS
© Georg Thieme Verlag Stuttgart · New York

2228
C. Gaulon et al.
PAPER
NHR1
O
H
O
H
O
NHR1
Cl
Br
O
(i)
(ii)
N
N
N
Cl
N
N
H
N
H
3a,d
–g
2a,d–g
(iii)
R1
R1
(iv)
NHR1
NHR2
N
N
(v)
N
N
N
O
O
R3HN
N
R2
N
R2
N
Cl
Cl
N
N
1a–
g
5a,c–g
4a,c–g
Scheme 1 Reagents and conditions: (i) R1NH2, 160 °C; (ii) POCl3/Et3N, 120 °C or PhPOCl2/Et3N, 160 °C; (iii) R2NH2, HCl, H2O, EtOH,
reflux; (iv) triphosgene, Et3N, THF, 0 °C–reflux; (v) for 1a,c–g: MeNH2, EtOH, microwaves, 140 °C; for 1b: PhNH2, HCl, H2O, EtOH, micro-
waves, 140 °C.
Table 1 Yields Obtained for the Synthesis of 6-Deoxypurin-8-ones 1
Compound
R1
R2
R3
2
3
4
5
Yield (%) of 1
a
b
c
d
e
f
Benzyl
CH3
CH3
Ph
CH3
Ph
90
90
90
94
92
91
91
18a
92
92
50
100
100
100
100
90
74
81
87
87
95
82
96
Benzyl
18a
Benzyl
CH3
CH3
CH3
CH3
CH3
18a
2-Fluorobenzyl
4-Fluorobenzyl
2,4-Difluorobenzyl
Phenylethyl
CH3
CH3
CH3
CH3
23a
100
90
14,a 23b
12a
91
100
100
g
33a
90
a POCl3, Et3N, 120 °C.
b PhPOCl2, Et3N, 160 °C.
fication method allowed us to perform this step on a mul- NMR spectroscopy). We managed to isolate pure 4c in
tigram scale, meaning that this step is suitable for scale-up 50% yield.
procedures.
The next step of the synthesis consisted of forming the cy-
To prepare 4,5-dialkylaminopyrimidine derivatives 4 se- clic urea of the purin-8-one skeleton. This was conve-
lectively, we took advantage of the difference in reactivity niently achieved in quantitative yields by using
of the 2- and 4-chloro substituents of 3 towards nucleo- triphosgene12 in THF (Scheme 1, 5a,c–g, Table 1).
philic substitution (Scheme 1). Indeed, reacting 3a and Whereas triphosgene reacted rapidly with the first amino
3d–g with an excess of methylamine in an acidic mixture functionality (presumably the more nucleophilic 5-amino
of EtOH and water11 afforded the expected 2-chloro-4- substituent) at room temperature to form a non-cyclised
methylamino derivatives 4a,d–g as the sole products and intermediate,13 heating to reflux was required for com-
in high yields (Table 1). Surprisingly, when the reaction plete cyclisation into purin-8-ones 5.
was conducted under the same conditions with excess
Finally, the chlorine atom in position 2, made more labile
aniline, a weaker nucleophile compared to primary alkyl-
amines, we observed the formation of a mixture of the ex-
pected 4-anilino-2-chloro derivative 4c with the 2,4-
dianilino derivative in a ratio of 7:3. Apparently, unlike
initially observed that the substitution of this final chlo-
the case of the 4-methylamino derivatives, the electron-
donating ability of the 4-anilino substituent proves to be
insufficient to completely deactivate the 2-chloro position
72 hours was required for full conversion as assessed by
towards nucleophilic substitution by a second molecule of
aniline. However, using one equivalent of aniline instead
amine under microwave irradiation14 at 140 °C dramati-
of an excess and extending the reaction time from one
by the urea formation as compared to 4 (Scheme 1), was
displaced by methylamine (1a, 1c–g, Table 1) or aniline
(1b, Table 1) to afford the desired products 1a–g. It was
rine occurred slowly when 5a was refluxed with 10 equiv-
alents of methylamine in EtOH. Under those conditions,
TLC. However, performing the reaction with methyl-
cally decreased the reaction time from 72 hours to 35
hour to 15 hours afforded 4c and the 2,4-dianilino product
minutes. Following this procedure, purin-8-ones 1a and
1
in a ratio of 10:1 with 64% conversion (according to H
1c–g were obtained in 74–96% isolated yields. Substitu-
Synthesis 2005, No. 13, 2227–2233 © Thieme Stuttgart · New York

PAPER
General and Facile Route to New Trisubstituted Purin-8-ones
2229
and washed successively with water and acetone, giving 2 in 90–
94% yield.
tion of the final chlorine by aniline failed to give 1b using
the same conditions as for methylamine. Aniline is appar-
ently not nucleophilic enough to displace the chlorine un-
der those conditions. Addition of two equivalents of silver
tetrafluoroborate to the reaction mixture (in order to facil-
itate the chlorine displacement by complexation) resulted
in only 77% conversion after 40 minutes under micro-
5-(Benzylamino)dihydropyrimidine-2,4(1H,3H)-dione (2a)
From 5-bromouracil (3.53 g, 18 mmol) and benzylamine (10.1 mL,
92 mmol, 5 equiv) 2a was obtained as a white solid (3.48 g, 90%).
1H NMR (250 MHz, DMSO-d6): d = 4.09 (d, J = 6.1 Hz, 2 H, CH2),
4.96 (t, J = 6.1 Hz, 1 H, NHCH2), 6.10 (d, J = 5.5 Hz, 1 H, H-6),
7.18–7.40 (m, 5 H, Ph), 10.02 (br s, 1 H, H-1), 11.14 (br s, 1 H, H-3).
1
wave irradiation at 140 °C (according to H NMR spec-
troscopy). Considering the disubstitution occurring when
3c was reacted with excess aniline (vide supra), we decid-
ed to use the same acidic aqueous medium (0.1 M aq HCl–
EtOH, 1:2) and a stoicheometric amount of aniline, under
microwave irradiation at 140 °C. Total conversion was
then achieved within 30 minutes and 4b was isolated in
81% yield. This new method appears to be a good alterna-
tive (faster and less expensive) for the palladium-cata-
lyzed cross-coupling reaction described by Ding et al.15
13C NMR (62.5 MHz, DMSO-d6): d = 46.8 (CH2), 112.8 (C-6),
123.2 (C-5), 126.7 (p-Ph), 127.0 (o-Ph), 128.2 (m-Ph), 139.2 (n-Ph),
149.1 (C-2), 161.2 (C-4).
5-[(2-Fluorobenzyl)amino]dihydropyrimidine-2,4(1H,3H)-di-
one (2d)
From 5-bromouracil (5 g, 26 mmol) and 2-fluorobenzylamine (9
mL, 78 mmol, 3 equiv) 2d was obtained as an off-white solid (5.75
g, 94%).
1H NMR (250 MHz, DMSO-d6): d = 4.14 (d, J = 6.4 Hz, 2 H, CH2),
4.90 (t, J = 6.4 Hz, 1 H, NHCH2), 6.21 (s, 1 H, H-6), 7.12–7.39 (m,
4 H, H-arom), 10.06 (br s, 1 H, H-1), 11.16 (br s, 1 H, H-3).
In conclusion, we describe here a facile and general route
to access a variety of new trisubstituted purin-8-ones 1,
starting from the cheap commercially available 5-bro-
mouracil. Although the dichlorination step gives rather
13C NMR (62.5 MHz, DMSO-d6): d = 40.5 (CH2), 113.1 (C-6),
114.9 (d, JC–F = 21.4 Hz, C-c), 123.0 (C-5), 124.3 (d, JC–F = 3.2 Hz,
disappointing yields, this reaction using cheap and readily C-e), 125.7 (d, JC–F = 14.5 Hz, C-a), 128.7 (d, JC–F = 8.2 Hz, C-d or
C-f), 129.2 (d, JC–F = 4.6 Hz, C-d or C-f), 149.2 (C-2), 160.0 (d,
JC–F = 243.6 Hz, C-b), 161.2 (C-4).
available starting materials can be easily performed on a
large scale. All other steps are reproducible and high
yielding and can be easily extended to a wide range of
amino functionalities. In addition, this route is suitable for
5-[(4-Fluorobenzyl)amino]dihydropyrimidine-2,4(1H,3H)-di-
one (2e)
the introduction of substituents other than amines at posi-
From 5-bromouracil (5 g, 26 mmol) and 4-fluorobenzylamine (11.9
tion C-2 (like aryl or aryloxy functionalities14,15) making
mL, 104 mmol, 4 equiv) 2e was obtained as a white solid (5.6 g,
92%).
this scaffold even more versatile. Thus, these new trisub-
stituted purin-8-ones possess key hydrogen donating/ac-
cepting functionalities for binding to biological targets.
This makes them and their range of readily accessible de-
rivatives potentially interesting compounds for medicinal
chemistry purposes.
1H NMR (250 MHz, DMSO-d6): d = 4.07 (d, J = 6.3 Hz, 2 H, CH2),
5.01 (t, J = 6.3 Hz, 1 H, NHCH2), 6.11 (s, 1 H, H-6), 7.13 (t, J = 8.8
Hz, 2 H, H-c, H-e), 7.34 (dd, J = 8.8, 5.6 Hz, 2 H, H-b, H-f), 10.06
(br s, 1 H, H-1), 11.11 (br s, 1 H, H-3).
13C NMR (62.5 MHz, DMSO-d6): d = 46.0 (CH2), 113.0 (C-6),
115.0 (d, JC–F = 21.1 Hz, C-c, C-e), 123.1 (C-5), 128.9 (d, JC–F = 8.0
Hz, C-b, C-f), 135.4 (d, JC–F = 3.0 Hz, C-a), 149.2 (C-2), 161.0 (d,
JC–F = 242.0 Hz, C-d), 161.3 (C-4).
Anhydrous THF (packed under N2) was purchased from Aldrich.
POCl3 was redistilled prior to use. Et3N was dried over KOH and re-
distilled prior to use. Microwave-assisted synthesis was performed
with the CEM Focused MicrowaveTM synthesis system, model Dis-
cover (parameters: power = 220 W, Pallowed = 200 psi for T = 140
°C). The applied wattage is continuously adjusted to maintain the
desired temperature. Reactions were conducted in their proprietary
5 mL sealed vials. Chromatography was performed with 40–60 mm
Merck Si-60 silica gel under medium pressure (1 bar). TLC was per-
formed on precoated sheets of Kieselgel 60 F254 (Merck). Low-res-
olution EI and FAB spectra were performed on a VG-2AB-SE
double focusing magnetic sector mass spectrometer (Fisons Instru-
ments), operating at a resolution of 1000. High-resolution accurate
mass spectra were determined on the same system, but with a reso-
lution set to 8000–10000. 1H NMR and 13C NMR spectra were re-
corded on a Bruker AC250 spectrometer in DMSO-d6 using TMS
as a reference. Chemical shifts (d) are given in ppm. Elemental anal-
yses were determined by Butterworth Laboratories Ltd. (Tedding-
ton, Middlesex, UK).
5-[(2,4-Difluorobenzyl)amino]dihydropyrimidine-2,4(1H,3H)-
dione (2f)
From 5-bromouracil (1.9 g, 9.98 mmol) and 2,4-difluorobenzyl-
amine (5 g, 34.9 mmol, 3.5 equiv) 2f was obtained as an off-white
solid (2.3 g, 91%).
1H NMR (250 MHz, DMSO-d6): d = 4.10 (d, J = 6.3 Hz, 2 H, CH2),
4.95 (t, J = 6.3 Hz, 1 H, NHCH2), 6.22 (d, J = 4.6 Hz, 1 H, H-6),
7.04 (td, J = 8.5, 2.5 Hz, 1 H, H-c), 7.20 (ddd, J = 10.6, 9.5, 2.5 Hz,
1 H, H-e), 7.38 (td, J = 8.5, 7.0 Hz, 1 H, H-f), 10.11 (br s, 1 H, H-
1), 11.20 (br s, 1 H, H-3).
13C NMR (62.5 MHz, DMSO-d6): d = 40.0 (CH2), 103.6 (t, JC–F
25.9 Hz, C-c), 111.3 (dd, JC–F = 21.1, 3.9 Hz, C-e), 113.2 (C-6),
122.1 (dd, JC–F = 14.9, 3.7 Hz, C-a), 122.9 (C-5), 130.4 (dd, JC–F
9.6, 6.4 Hz, C-f), 149.3 (C-2), 160.0 (d, JC–F = 246.4 Hz, C-b), 161.0
(d, JC–F = 245.0 Hz, C-d), 161.2 (C-4).
=
=
5-[(2-Phenylethyl)amino]dihydropyrimidine-2,4(1H,3H)-dione
(2g)
From 5-bromouracil (5 g, 26 mmol) and phenethylamine (16.3 mL,
130 mmol, 5 equiv) 2g was obtained as an off-white solid (5.43 g,
91%).
5-[(Aralkyl)amino]dihydropyrimidine-2,4(1H,3H)-diones (2);
General Procedure
A mixture of 5-bromouracil (1 equiv, 10–26 mmol) and alkylamine
(3–5 equiv) was heated at 160 °C for 2 h. After cooling to r.t., the
mixture was poured into water (40 mL) and the pH was adjusted to
7 by addition of 1 N HCl. The precipitate was collected by filtration
1H NMR (250 MHz, DMSO-d6): d = 2.81 (t, J = 7.1 Hz, 2 H,
CH2Ph), 3.04 (q, J = 6.9 Hz, 2 H, CH2NH), 4.16 (t, J = 6.1 Hz, 1 H,
Synthesis 2005, No. 13, 2227–2233 © Thieme Stuttgart · New York

2230
C. Gaulon et al.
PAPER
NHCH2), 6.37 (s, 1 H, H-6), 7.15–7.32 (m, 5 H, Ph), 10.20 (br s, 1
H, H-1), 11.06 (br s, 1 H, H-3).
JC–F = 3.0 Hz, C-a), 138.0 (C-5), 140.8 (C-6), 143.4 (C-4), 145.0 (C-
2), 161.2 (d, JC–F = 242.7 Hz, C-d).
13C NMR (62.5 MHz, DMSO-d6): d = 34.2 (CH2Ph), 44.8
(CH2NH), 112.8 (C-6), 123.6 (C-5), 126.0 (p-Ph), 128.2 (o-Ph),
128.6 (m-Ph), 139.6 (n-Ph), 149.3 (C-2), 161.2 (C-4).
HRMS (EI): m/z [M + H]+ calcd for C11H9N3FCl2: 272.0158; found:
272.0189.
2,4-Dichloro-N-(2,4-difluorobenzyl)pyrimidin-5-amine (3f)
From 2f (3 g, 11.8 mmol), performing the reaction at 120 °C for 2.5
h, 3f (360 mg, 12%) was obtained as a yellow solid after chroma-
tography on silica gel (petroleum ether–Et2O, 8:2 → 7:3); Rf 0.39
(petroleum ether–Et2O, 1:1).
N-Benzyl-2,4-dichloropyrimidin-5-amine (3a); Typical Proce-
dure
POCl3 (7.7 mL, 82 mmol) was slowly added to a mixture of 2a (1.78
g, 8.2 mmol) and Et3N (2.5 mL, 18 mmol) at 0 °C under a N2 atmo-
sphere. The mixture was stirred at 120 °C for 15 h and the excess of
POCl3 was removed in vacuo. The resulting brown residue was di-
luted with CH2Cl2 (40 mL) and poured into flaked ice (about 25 g)
whilst stirring vigorously. The pH was adjusted to 7 by careful ad-
dition of a sat. aq solution of Na2CO3. The aqueous layer was ex-
tracted with CH2Cl2 (3 × 30 mL) and the combined organic layer
was washed with water (2 × 40 mL) and dried over MgSO4. Evap-
oration of the solvent under reduced pressure led to a brown residue
which was purified by chromatography on silica gel (petroleum
ether–Et2O, 9:1 → 7:3) to afford 3a (362 mg, 18%) as a pale yellow
solid; Rf 0.40 (petroleum ether–Et2O, 1:1).
1H NMR (250 MHz, DMSO-d6): d = 4.49 (d, J = 5.3 Hz, 2 H, CH2),
6.81 (t, J = 5.3 Hz, 1 H, NHCH2), 7.04 (tdd, J = 8.5, 2.6, 1.0 Hz, 1
H, H-c), 7.25 (ddd, J = 10.6, 9.2, 2.6 Hz, 1 H, H-e), 7.37 (td, J = 8.7,
6.6 Hz, 1 H, H-f), 8.01 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 39.0 (CH2), 103.8 (t, JC–F
=
26.0 Hz, C-c), 111.3 (dd, JC–F = 20.8, 3.5 Hz, C-e), 120.9 (dd,
JC–F = 14.8, 3.5 Hz, C-a), 130.0 (dd, JC–F = 9.9, 5.7 Hz, C-f), 137.9
(C-5), 140.7 (C-6), 143.6 (C-4), 145.0 (C-2), 160.2 (d, JC–F = 247.4
Hz, C-b), 161.5 (d, JC–F = 245.5 Hz, C-d).
HRMS (EI): m/z [M + H]+ calcd for C11H8N3F2Cl2: 290.0063;
found: 290.0066.
1H NMR (250 MHz, DMSO-d6): d = 4.48 (d, J = 6.2 Hz, 2 H, CH2),
6.96 (t, J = 6.2 Hz, 1 H, NHCH2), 7.20–7.40 (m, 5 H, Ph), 7.94 (s,
1 H, H-6).
2,4-Dichloro-N-(2-phenylethyl)pyrimidin-5-amine (3g)
From 2g (1.5 g, 6.5 mmol), 3g (589 mg, 33%) was obtained as a yel-
low solid after chromatography on silica gel (petroleum ether–Et2O,
9:1 → 8:2); Rf 0.34 (petroleum ether–Et2O, 1:1).
13C NMR (62.5 MHz, DMSO-d6): d = 45.0 (CH2), 126.8 (p-Ph),
127.0 (o-Ph), 128.4 (m-Ph), 137.8 (n-Ph or C-5), 138.0 (n-Ph or C-
5), 140.8 (C-6), 143.2 (C-4), 144.9 (C-2).
1H NMR (250 MHz, DMSO-d6): d = 2.87 (t, J = 6.9 Hz, 2 H,
CH2Ph), 3.45 (t, J = 6.9 Hz, 2 H, CH2NH), 6.16 (br s, 1 H, NHCH2),
7.13–7.43 (m, 5 H, Ph), 8.18 (s, 1 H, H-6).
HRMS (EI): m/z [M + H]+ calcd for C11H10N3Cl2: 254.0252; found:
254.0238.
13C NMR (62.5 MHz, DMSO-d6): d = 34.2 (CH2Ph), 43.5
(CH2NH), 126.1 (p-Ph), 128.2 (o-Ph), 128.7 (m-Ph), 138.3, 139.0
(n-Ph, C-5), 140.8 (C-6), 142.9 (C-4), 144.5 (C-2).
2,4-Dichloro-N-(2-fluorobenzyl)pyrimidin-5-amine (3d)
From 2d (3 g, 12.7 mmol), performing the reaction at 120 °C for 2.5
h, 3d (770 mg, 23%) was obtained as yellow crystals after chroma-
tography on silica gel (petroleum ether–Et2O, 8:2 → 1:1); Rf 0.54
(petroleum ether–Et2O, 1:1).
HRMS (EI): m/z [M + H]+ calcd for C12H12N3Cl2: 268.0408; found:
268.0455.
1H NMR (250 MHz, DMSO-d6): d = 4.54 (d, J = 5.7 Hz, 2 H, CH2),
6.83 (t, J = 5.7 Hz, 1 H, NHCH2), 7.12–7.37 (m, 4 H, H-arom), 7.99
(s, 1 H, H-6).
N5-Benzyl-2-chloro-N4-methylpyrimidine-4,5-diamine (4a);
Typical Procedure
To a solution of 3a (200 mg, 0.79 mmol) in EtOH (3 mL) were add-
ed 0.1 M aq HCl (5 mL) and methylamine (33 weight% in EtOH, 1
mL, 7.9 mmol). The mixture was heated at reflux for 1 h and con-
centrated under reduced pressure until crystals appeared in the flask
(2 mL). The crystals were collected by filtration and washed with
water to afford 4a (180 mg, 92%) as an off-white solid.
13C NMR (62.5 MHz, DMSO-d6): d = 39.3 (CH2), 115.2 (d, JC–F
=
20.9 Hz, C-c), 124.4 (d, JC–F = 3.5 Hz, C-e), 124.5 (d, JC–F = 14.2
Hz, C-a), 128.7 (d, JC–F = 4.4 Hz, C-d or C-f), 129.1 (d, JC–F = 8.3
Hz, C-d or C-f), 138.0 (C-5), 140.7 (C-6), 143.5 (C-4), 145.0 (C-2),
160.0 (d, JC–F = 244.3 Hz, C-b).
HRMS (EI): m/z [M + H]+ calcd for C11H9N3FCl2: 272.0158; found:
272.0185.
1H NMR (250 MHz, DMSO-d6): d = 2.86 (d, J = 4.5 Hz, 3 H, CH3),
4.27 (d, J = 5.4 Hz, 2 H, CH2), 5.44 (t, J = 5.4 Hz, 1 H, NHCH2),
7.18 (s, 1 H, H-6), 7.25–7.40 (m, 6 H, Ph, NHCH3).
2,4-Dichloro-N-(4-fluorobenzyl)pyrimidin-5-amine (3e)
PhPOCl2 (2.5 mL, 17.3 mmol) was added to a suspension of 2e (1
g, 4.3 mmol) in Et3N (1.3 mL, 9.5 mmol) and the mixture was heat-
ed at 160 °C for 2 h. After cooling, the solution was poured into a
mixture of flaked ice (80 g) and EtOAc (80 mL) and stirring was
continued for 30 min. The organic layer was then washed with aq
sat. NaHCO3 (2 × 40 mL), water (2 × 40 mL) and dried over MgSO4.
The solvent was removed under reduced pressure and the residue
was chromatographed on silica gel (petroleum ether–Et2O, 8:2 →
7:3) to afford 3e (270 mg, 23%) as a pale yellow solid; Rf 0.27 (pe-
troleum ether–Et2O, 1:1).
13C NMR (62.5 MHz, DMSO-d6): d = 27.5 (CH3), 46.4 (CH2), 127.0
(C-5, p-Ph), 127.5 (o-Ph), 128.3 (m-Ph), 131.7 (C-6), 138.4 (n-Ph),
147.2 (C-2), 154.3 (C-4).
N5-Benzyl-2-chloro-N4-phenylpyrimidine-4,5-diamine (4c)
From 3c (100 mg, 0.39 mmol) and aniline (39 mL, 0.433 mmol),
heating the mixture at reflux for 15 h, 4c (60 mg, 50%) was isolated
as an off-white solid by washing the crude solid with H2O and
CHCl3.
1H NMR (250 MHz, DMSO-d6): d = 4.38 (s, 2 H, CH2), 7.08 (t, J =
7.3 Hz, 1 H, p-PhNH), 7.25–7.44 (m, 9 H, H-arom, H-6, NHCH2),
7.69 (d, J = 7.7 Hz, 2 H, o-PhNH), 9.08 (s, 1 H, NHPh).
1H NMR (250 MHz, DMSO-d6): d = 4.48 (d, J = 6.2 Hz, 2 H, CH2),
6.96 (t, J = 6.2 Hz, 1 H, NHCH2), 7.20–7.40 (m, 4 H, H-arom), 7.94
(s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 46.2 (CH2), 121.0 (o-PhN),
123.3 (p-PhN), 127.0 (C-5), 127.5, 127.7 (o-Ph, p-Ph), 128.4, 128.6
(m-Ph, m-PhN), 133.1 (C-6), 138.2, 138.8 (n-PhN, n-Ph), 144.9 (C-
2), 150.5 (C-4).
13C NMR (62.5 MHz, DMSO-d6): d = 44.3 (CH2), 115.2 (d, JC–F
21.3 Hz, C-c, C-e), 129.0 (d, JC–F = 8.1 Hz, C-b, C-f), 134.0 (d,
=
Synthesis 2005, No. 13, 2227–2233 © Thieme Stuttgart · New York

PAPER
General and Facile Route to New Trisubstituted Purin-8-ones
2231
2-Chloro-N5-(2-fluorobenzyl)-N4-methylpyrimidine-4,5-di-
amine (4d)
From 3d (200 mg, 0.73 mmol) 4d (196 mg, 100%) was obtained as
a white solid.
13C NMR (62.5 MHz, DMSO-d6): d = 26.2 (CH3), 44.2 (CH2), 122.0
(C-5), 127.5 (p-Ph), 127.7 (o-Ph), 128.6 (m-Ph), 133.4 (C-6), 135.6
(n-Ph), 150.7, 151.2, 152.6 (C-2, C-4, C=O).
7-Benzyl-2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one (5c)
From 4c (55 mg, 0.18 mmol) 5c (59 mg, 100%) was obtained as a
white solid.
1H NMR (250 MHz, DMSO-d6): d = 2.85 (d, J = 4.5 Hz, 3 H,
CH3NH), 4.30 (d, J = 5.4 Hz, 2 H, CH2), 5.39 (t, J = 5.4 Hz, 1 H,
NHCH2), 7.15–7.45 (m, 6 H, H-arom, H-6, NHCH3).
1H NMR (250 MHz, DMSO-d6): d = 5.16 (s, 2 H, CH2), 7.30–7.67
(m, 10 H, H-arom), 8.39 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 27.4 (CH3), 40.2 (CH2), 115.2
(d, JC–F = 21.0 Hz, C-c), 124.3 (d, JC–F = 3.5 Hz, C-e), 125.0 (d,
JC–F = 14.2 Hz, C-a), 126.9 (C-5), 129.2 (d, JC–F = 4.5 Hz, C-d or C-
f), 129.9 (d, JC–F = 8.5 Hz, C-d or C-f), 131.6 (C-6), 147.4 (C-2),
154.3 (C-4), 160.4 (d, JC–F = 244.3 Hz, C-b).
13C NMR (62.5 MHz, DMSO-d6): d = 44.5 (CH2), 122.2 (C-5),
126.5 (o-PhN), 127.7 and 127.8 (o-Ph, p-Ph), 128.5 and 128.7 (m-
Ph, p-PhN), 129.1 (m-PhN), 131.9 (C-6), 134.4 and 135.4 (n-PhN,
(n-Ph), 150.7, 150.9 and 151.6 (C-2, C-4, C=O).
2-Chloro-N5-(4-fluorobenzyl)-N4-methylpyrimidine-4,5-di-
amine (4e)
From 3e (170 mg, 0.62 mmol) 4e (150 mg, 90%) was obtained as an
off-white solid.
2-Chloro-7-(2-fluorobenzyl)-9-methyl-7,9-dihydro-8H-purin-8-
one (5d)
From 4d (180 mg, 0.67 mmol) 5d (197 mg, 100%) was obtained as
a white solid.
1H NMR (250 MHz, DMSO-d6): d = 2.85 (d, J = 4.5 Hz, 3 H,
CH3NH), 4.25 (d, J = 5.4 Hz, 2 H, CH2), 5.42 (t, J = 5.4 Hz, 1 H,
NHCH2), 7.18 (m, 4 H, H-c, H-e, H-6, NHCH3), 7.39 (dd, J = 5.7,
8.4 Hz, 2 H, H-b, H-f).
1H NMR (250 MHz, DMSO-d6): d = 3.33 (s, 3 H, CH3), 5.14 (s, 2
H, CH2), 7.14–7.42 (m, 4 H, H-arom), 8.24 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 26.2 (CH3), 38.9 (CH2), 115.4
(d, JC–F = 20.8 Hz, C-c), 122.1 (C-5), 122.3 (d, JC–F = 14.8 Hz, C-a),
124.5 (d, JC–F = 3.5 Hz, C-e), 129.9 (d, JC–F = 4.0 Hz, C-d or C-f),
130.0 (d, JC–F = 8.2 Hz, C-d or C-f), 133.5 (C-6), 150.7, 151.3, 152.4
(C-2, C-4, C=O), 160.0 (d, JC–F = 246.0 Hz, C-b).
13C NMR (62.5 MHz, DMSO-d6): d = 27.4 (CH3), 45.6 (CH2), 115.0
(d, JC–F = 21.2 Hz, C-c, C-e), 126.9 (C-5), 129.4 (d, JC–F = 8.1 Hz,
C-b, C-f), 131.8 (C-6), 134.5 (d, JC–F = 3.0 Hz, C-a), 147.0 (C-2),
154.4 (C-4), 161.0 (d, JC–F = 243.0 Hz, C-d).
2-Chloro-N5-(2,4-difluorobenzyl)-N4-methylpyrimidine-4,5-di-
amine (4f)
2-Chloro-7-(4-fluorobenzyl)-9-methyl-7,9-dihydro-8H-purin-8-
one (5e)
From 3f (250 mg, 0.86 mmol) 4f (221 mg, 91%) was obtained as an
off-white solid.
From 4e (116 mg, 0.43 mmol) 5e (114 mg, 90%) was obtained as a
white solid.
1H NMR (250 MHz, DMSO-d6): d = 2.85 (d, J = 4.5 Hz, 3 H,
CH3NH), 4.27 (d, J = 5.3 Hz, 2 H, CH2), 5.33 (t, J = 5.3 Hz, 1 H,
NHCH2), 7.04–7.34 (m, 4 H, H-c, H-e, H-6, NHCH3), 7.46 (td, J =
8.6, 6.9 Hz, 1 H, H-f).
1H NMR (250 MHz, DMSO-d6): d = 3.33 (s, 3 H, CH3), 5.07 (s, 2
H, CH2), 7.18 (t, J = 8.8 Hz, 2 H, H-c, H-e), 7.42 (dd, J = 5.5, 8.4
Hz, 2 H, H-b, H-f), 8.29 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 26.2 (CH3), 43.5 (CH2), 115.4
(d, JC–F = 21.4 Hz, C-c, C-e), 121.9 (C-5), 129.8 (d, JC–F = 8.4 Hz,
C-b, C-f), 131.9 (d, JC–F = 3.1 Hz, C-a), 133.4 (C-6), 150.7; 151.3,
152.6 (C-2, C-4, C=O), 161.0 (d, JC–F = 243.0 Hz, C-d).
13C NMR (62.5 MHz, DMSO-d6): d = 27.4 (CH3), 39.9 (CH2), 103.7
(t, JC–F = 25.7 Hz, C-c), 111.2 (dd, JC–F = 21.1, 3.6 Hz, C-e), 121.4
(dd, JC–F = 14.8, 3.5 Hz, C-a), 126.8 (C-5), 131.1 (dd, JC–F = 9.8, 6.1
Hz, C-f), 131.7 (C-6), 147.5 (C-2), 154.3 (C-4), 160.0 (d, JC–F
247.4 Hz, C-b), 161.0 (d, JC–F = 245.5 Hz, C-d).
=
2-Chloro-7-(2,4-difluorobenzyl)-9-methyl-7,9-dihydro-8H-pu-
rin-8-one (5f)
2-Chloro-N4-methyl-N5-(2-phenylethyl)pyrimidine-4,5-di-
amine (4g)
From 4f (200 mg, 0.70 mmol) 5f (218 mg, 100%) was obtained as
a white solid.
From 3g (200 mg, 0.74 mmol) 4g (176 mg, 90%) was obtained as a
pale yellow solid.
1H NMR (250 MHz, DMSO-d6): d = 3.31 (s, 3 H, CH3), 5.11 (s, 2
H, CH2), 7.06 (tdd, J = 8.5, 2.6, 1.0 Hz, 1 H, H-c), 7.28 (ddd, J =
10.6, 9.3, 2.5 Hz, 1 H, H-e), 7.46 (td, J = 8.7, 6.6 Hz, 1 H, H-f), 8.26
(s, 1 H, H-6).
1H NMR (250 MHz, DMSO-d6): d = 2.85 (d, J = 4.4 Hz, 3 H,
CH3NH), 2.87 (t, J = 7.7 Hz, 2 H, CH2Ph), 3.25 (td, J = 7.7, 5.2 Hz,
2 H, CH2NH), 4.96 (t, J = 5.2 Hz, 1 H, NHCH2), 7.06–7.41 (m, 7 H,
Ph, H-6, NHCH3).
13C NMR (62.5 MHz, DMSO-d6): d = 26.2 (CH3), 39.5 (CH2), 104.0
(t, JC–F = 25.8 Hz, C-c), 111.4 (dd, JC–F = 21.3, 3.6 Hz, C-e), 118.8
(dd, JC–F = 15.1, 3.6 Hz, C-a), 122.0 (C-5), 131.3 (dd, JC–F = 10.0,
5.5 Hz, C-f), 133.4 (C-6), 150.7, 151.3, 152.4 (C-2, C-4, C=O),
160.1 (dd, JC–F = 248.5, 12.5 Hz, C-b), 161.0 (d, JC–F = 246.6, 12.0
Hz, C-d).
13C NMR (62.5 MHz, DMSO-d6): d = 27.5 (CH3), 34.3 (CH2Ph),
44.4 (CH2NH), 126.1 (p-Ph), 127.3 (C-5), 128.2 (o-Ph), 128.7 (m-
Ph), 131.2 (C-6), 139.4 (n-Ph), 147.0 (C-2), 154.2 (C-4).
7-Benzyl-2-chloro-9-methyl-7,9-dihydro-8H-purin-8-one (5a);
Typical Procedure
2-Chloro-9-methyl-7-(2-phenyletyl)-7,9-dihydro-8H-purin-8-
one (5g)
From 4g (150 mg, 0.57 mmol) 5g (164 mg, 100%) was obtained as
a white solid.
To a solution of 4a (170 mg, 0.68 mmol) and Et3N (0.2 mL, 1.43
mmol) in THF (5 mL), at 0 °C under a N2 atmosphere, was added a
solution of triphosgene (202 mg, 0.68 mmol) in THF (5 mL). The
mixture was allowed to warm to r.t. and then heated at reflux over-
night. The solution was cooled to r.t., filtrated over cotton to remove
the ammonium salts and the solvent was evaporated under reduced
pressure. The obtained crystals were washed with a small amount of
cold EtOH to afford 5a (186 mg, 100%) as a pale pink powder.
1H NMR (250 MHz, DMSO-d6): d = 2.97 (t, J = 7.2 Hz, 2 H,
CH2Ph), 3.29 (s, 3 H, CH3), 4.09 (t, J = 7.2 Hz, 2 H, CH2N), 7.18–
7.29 (m, 5 H, Ph), 8.10 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 26.1 (CH3), 33.6 (CH2Ph),
42.5 (CH2N), 122.1 (C-5), 126.5 (p-Ph), 128.3 (o-Ph), 128.8 (m-
1H NMR (250 MHz, DMSO-d6): d = 3.34 (s, 3 H, CH3), 5.08 (s, 2
H, CH2), 7.28–7.40 (m, 5 H, Ph), 8.25 (s, 1 H, H-6).
Synthesis 2005, No. 13, 2227–2233 © Thieme Stuttgart · New York

2232
C. Gaulon et al.
PAPER
Ph), 133.6 (C-6), 137.9 (n-Ph), 150.3, 150.8, 152.4 (C-2, C-4,
C=O).
13C NMR (62.5 MHz, DMSO-d6): d = 25.6 (CH3N), 28.2 (CH3NH),
38.3 (CH2), 114.1 (C-5), 115.4 (d, JC–F = 21.0 Hz, C-c), 123.0 (d,
JC–F = 14.9 Hz, C-a), 124.5 (d, JC–F = 3.4 Hz, C-e), 129.8 (d, JC–F
=
7-Benzyl-9-methyl-2-(methylamino)-7,9-dihydro-8H-purin-8-
one (1a); Typical Procedure
6.7 Hz, C-d or C-f), 129.9 (d, JC–F = 5.4 Hz, C-d or C-f), 133.6 (C-
6), 150.6, 152.4 (C-4, C=O), 158.9 (C-2), 159.9 (d, JC–F = 245.5 Hz,
C-b).
To a solution of 5a (50 mg, 0.18 mmol) in EtOH (1 mL) was added
methylamine (33 weight% solution in EtOH, 0.45 mL, 3.6 mmol).
The vial was sealed and heated by microwave at 140 °C for 35 min.
After cooling to r.t., the solvent was evaporated in vacuo and the
residue was purified by silica gel chromatography (EtOAc–cyclo-
hexane, 3:2) to afford 1a (36 mg, 74%) as a white solid; Rf 0.18
(EtOAc–cyclohexane, 3:2).
Anal. Calcd for C14H14FN5O: C, 58.53; H, 4.91; F, 6.61; N, 24.38.
Found C, 58.35; H, 4.86; F, 6.55; N, 24.43.
7-(4-Fluorobenzyl)-9-methyl-2-(methylamino)-7,9-dihydro-8H-
purin-8-one (1e)
From 5e (109 mg, 0.37 mmol) 1e (100 mg, 95%) was obtained as a
white solid after silica gel chromatography (EtOAc–cyclohexane,
7:3); Rf 0.36 (EtOAc).
1H NMR (250 MHz, DMSO-d6): d = 2.74 (d, J = 4.8 Hz, 3 H,
CH3NH), 3.25 (s, 3 H, CH3N), 4.96 (s, 2 H, CH2), 6.73 (q, J = 4.8
Hz, 1 H, NHCH3), 7.23–7.40 (m, 5 H, Ph), 7.81 (s, 1 H, H-6).
1H NMR (250 MHz, DMSO-d6): d = 2.74 (d, J = 4.7 Hz, 3 H,
CH3NH), 3.24 (s, 3 H, CH3N), 4.95 (s, 2 H, CH2), 6.74 (q, J = 4.7
Hz, 1 H, NHCH3), 7.16 (t, J = 8.9 Hz, 2 H, H-c, H-e), 7.37 (dd, J =
5.6 Hz, 8.5 Hz, 2 H, H-b, H-f), 7.85 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 25.5 (CH3N), 28.1 (CH3NH),
43.8 (CH2), 114.1 (C-5), 127.4 (p-Ph, o-Ph), 128.5 (m-Ph), 133.7
(C-6), 136.4 (n-Ph), 150.5, 152.6 (C-4, C=O), 158.9 (C-2).
Anal. Calcd for C14H15N5O: C, 62.44; H, 5.61; N, 26.01. Found: C,
62.04; H, 5.61; N, 25.75.
13C NMR (62.5 MHz, DMSO-d6): d = 5.5 (CH3N), 28.1 (CH3NH),
43.1 (CH2), 114.0 (C-5), 115.3 (d, JC–F = 21.5 Hz, C-c, C-e), 129.6
(d, JC–F = 8.3 Hz, C-b, C-f), 132.7 (d, JC–F = 3.1 Hz, C-a), 133.7 (C-
6), 150.5, 152.5 (C-4, C=O), 159.0 (C-2), 161.4 (d, JC–F = 243.6 Hz,
C-d).
2-Anilino-7-benzyl-9-methyl-7,9-dihydro-8H-purin-8-one (1b)
To a solution of 5a (55 mg, 0.20 mmol) in EtOH (0.75 mL) were
added 0.1 M aq HCl (1.5 mL) and aniline (23 mL, 0.24 mmol). The
vial was sealed and heated by microwave at 140 °C for 1 h. After
cooling to r.t., the obtained crystals were collected by filtration and
washed with water and cold EtOH to afford 1b (53 mg, 81%) as a
white solid.
Anal. Calcd for C14H14FN5O: C, 58.53; H, 4.91; F, 6.61; N, 24.38.
Found: C, 58.32; H, 4.88; F, 6.90; N, 24.50.
7-(2,4-Difluorobenzyl)-9-methyl-2-(methylamino)-7,9-dihydro-
8H-purin-8-one (1f)
1H NMR (250 MHz, DMSO-d6): d = 3.33 (s, 3 H, CH3), 5.02 (s, 2
H, CH2), 6.88 (t, J = 7.2 Hz, 1 H, p-PhNH), 7.23 (t, J = 7.8 Hz, 1 H,
p-Ph), 7.29–7.40 (m, 6 H, H-arom), 7.75 (d, J = 8.3 Hz, 2 H, H-
arom), 8.00 (s, 1 H, H-6), 9.41 (s, 1 H, NH).
From 5f (100 mg, 0.32 mmol) 1f (81 mg, 82%) was isolated as a
white solid by filtration and washing with cold EtOH of the crystals
obtained while cooling the reaction mixture to r.t.
1H NMR (250 MHz, DMSO-d6): d = 2.75 (d, J = 4.7 Hz, 3 H,
CH3NH), 3.23 (s, 3 H, CH3N), 4.99 (s, 2 H, CH2), 6.75 (q, J = 4.7
Hz, 1 H, NHCH3), 7.06 (td, J = 8.5, 2.4 Hz, 1 H, H-c), 7.26 (ddd,
J = 10.5, 9.5, 2.5 Hz, 1 H, H-e), 7.39 (td, J = 8.6, 6.7 Hz, 1 H, H-f),
7.80 (s, 1 H, H-6).
13C NMR (62.5 MHz, DMSO-d6): d = 25.8 (CH3), 43.9 (CH2), 115.8
(C-5), 117.9 (o-PhNH), 120.4 (p-PhNH), 127.5 (p-Ph, o-Ph), 128.2,
128.5 (m-Ph, m-PhNH), 133.0 (C-6), 136.2 (n-Ph), 140.9 (n-PhNH),
150.2, 152.6 (C-4, C=O), 155.0 (C-2).
Anal. Calcd for C19H17N5O: C, 68.87; H, 5.17; N, 21.13. Found: C,
68.49; H, 5.14; N, 21.18.
13C NMR (62.5 MHz, DMSO-d6): d = 25.5 (CH3N), 28.2 (CH3NH),
37.9 (d, JC–F = 3.3 Hz, CH2), 104.0 (t, JC–F = 25.7 Hz, C-c), 111.5
(dd, JC–F = 21.3, 3.7 Hz, C-e), 114.0 (C-5), 119.5 (dd, JC–F = 15.2,
3.7 Hz, C-a), 131.2 (dd, JC–F = 9.9, 5.7 Hz, C-f), 133.7 (C-6), 150.6,
152.4 (C-4, C=O), 158.9 (C-2), 160.0 (dd, JC–F = 248.5, 12.6 Hz, C-
b), 161.9 (d, JC–F = 246.3, 12.0 Hz, C-d).
7-Benzyl-2-(methylamino)-9-phenyl-7,9-dihydro-8H-purin-8-
one (1c)
From 5c (59 mg, 0.17 mmol) 1c (51 mg, 87%) was obtained as a
white solid after silica gel chromatography (EtOAc–cyclohexane,
2:3 → 1:1); Rf 0.37 (EtOAc–cyclohexane, 3:2).
Anal. Calcd for C14H13F2N5O: C, 55.08; H, 4.29; F, 12.45; N, 22.94.
Found: C, 54.87; H, 4.29; F, 12.29; N, 23.06.
1H NMR (250 MHz, DMSO-d6): d = 2.70 (d, J = 4.8 Hz, 3 H,
CH3NH), 5.05 (s, 2 H, CH2), 6.75 (q, J = 4.8 Hz, 1 H, NHCH3),
7.28–7.75 (m, 10 H, H-arom), 7.95 (s, 1 H, H-6).
9-Methyl-2-(methylamino)-7-(2-phenylethyl)-7,9-dihydro-8H-
purin-8-one (1g)
From 5g (144 mg, 0.50 mmol) 1g (137 mg, 96%) was obtained as a
white solid after silica gel chromatography (EtOAc–cyclohexane,
7:3); Rf 0.15 (EtOAc–cyclohexane, 7:3).
13C NMR (62.5 MHz, DMSO-d6): d = 28.0 (CH3), 44.0 (CH2), 113.9
(C-5), 126.2 (o-PhN, p-PhN), 127.5 (o-Ph, p-Ph), 128.5, 128.7 (m-
Ph, m-PhN), 132.8 (C-6), 134.7 (n-PhN), 136.2 (n-Ph), 150.0, 151.4
(C-4, C=O), 159.0 (C-2).
1H NMR (250 MHz, DMSO-d6): d = 2.75 (d, J = 4.8 Hz, 3 H,
CH3NH), 2.93 (t, J = 7.2 Hz, 2 H, CH2Ph), 3.18 (s, 3 H, CH3N), 3.98
(t, J = 7.2 Hz, 2 H, CH2N), 6.68 (q, J = 4.8 Hz, 1 H, NHCH3), 7.16–
7.29 (m, 5 H, Ph), 7.78 (s, 1 H, H-6).
Anal. Calcd for C19H17N5O: C, 68.87; H, 5.17; N, 21.13. Found: C,
68.36; H, 5.01; N, 21.12.
7-(2-Fluorobenzyl)-9-methyl-2-(methylamino)-7,9-dihydro-8H-
purin-8-one (1d)
From 5d (100 mg, 0.34 mmol) 1d (85 mg, 87%) was isolated as a
white solid by filtration and washing with cold EtOH of the crystals
obtained while cooling the reaction mixture to r.t.
13C NMR (62.5 MHz, DMSO-d6): d = 25.4 (CH3N), 28.2 (CH3NH),
33.8 (CH2Ph), 42.0 (CH2N), 114.3 (C-5), 126.3 (p-Ph), 128.2 (o-
Ph), 128.7 (m-Ph), 133.7 (C-6), 138.2 (n-Ph), 150.2, 152.4 (C-4,
C=O), 158.7 (C-2).
Anal. Calcd for C15H17N5O: C, 63.59; H, 6.05; N, 24.72. Found: C,
63.24; H, 6.02; N, 24.62.
1H NMR (250 MHz, DMSO-d6): d = 2.74 (d, J = 4.8 Hz, 3 H,
CH3NH), 3.24 (s, 3 H, CH3N), 5.02 (s, 2 H, CH2), 6.75 (q, J = 4.8
Hz, 1 H, NHCH3), 7.13–7.41 (m, 4 H, H-arom), 7.78 (s, 1 H, H-6).
Synthesis 2005, No. 13, 2227–2233 © Thieme Stuttgart · New York

PAPER
General and Facile Route to New Trisubstituted Purin-8-ones
2233
Otyepka, M.; Strnad, M. Bioorg. Med. Chem. Lett. 2003, 13,
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Acknowledgment
We would like to thank Cancer Research-UK (grant numbers C309/
A2187 and C107/A3096), the Institute of Cancer Research and
Wellcome Trust for the funding of this work. We are grateful to our
colleagues Lawrence Davies, Dan Niculescu-Duvaz, Ion Nicules-
cu-Duvaz, Esteban Roman and Ian Scanlon (at the ICR) and to Ri-
chard Taylor and Adrian Gill (Astex Technology Ltd) for fruitful
discussions.
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Synthesis 2005, No. 13, 2227–2233 © Thieme Stuttgart · New York