Synthesis of 6-cyano and 6-unsubstituted 2-aryl-8-oxopurine from a common 2-oxoimidazole precursor

Article abstract of DOI:10.1016/j.tet.2010.11.064

The benzyl urea of diaminomaleonitrile, prepared from commercially available starting materials, was reacted with aromatic aldehydes at room temperature. Intramolecular cyclization of the product, in basic solution, generated a substituted 2-oxoimidazole.

Full text of DOI:10.1016/j.tet.2010.11.064

Tetrahedron 67 (2011) 755e762
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Synthesis of 6-cyano and 6-unsubstituted 2-aryl-8-oxopurine from a common
2-oxoimidazole precursor
*
Magdi E.A. Zaki, M. Fernanda Proenc¸ a
Departmento de Quimica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 October 2010
Received in revised form 9 November 2010
Accepted 15 November 2010
Available online 20 November 2010
The benzyl urea of diaminomaleonitrile, prepared from commercially available starting materials, was
reacted with aromatic aldehydes at room temperature. Intramolecular cyclization of the product, in basic
solution, generated a substituted 2-oxoimidazole. This compound proved to be a common precursor for
2-aryl-6-cyano-8-oxopurines upon treatment with acid and for 2-aryl-6-unsubstituted-8-oxopurines, in
the presence of base. A 1H NMR study of these simple and versatile reactions supports the mechanistic
proposal.
Keywords:
Diaminomaleonitrile
Aldehyde
Ó 2010 Published by Elsevier Ltd.
Urea derivatives
Oxoimidazole
Oxopurine
1. Introduction
cyclization through nucleophilic attack by the neighbouring sec-
ondary amine.
The purine scaffold is a key component in an increasing number
of biologically active compounds.1 Derivatives incorporating the
aryl substituent in the 2-position have recently attracted much
attention due to their potential biological activity namely as in-
terferon inducers,2 c-AMP phosphodiesterase inhibitors,3 sulfo-
transferase inhibitors,4 A1 adenosine receptor ligands5,6 and
adenosine deaminase ligands.6a
The synthesis of 2-arylpurine derivatives classically involves
ring construction of the imidazole moiety from a 2-aryl-4,5-dia-
minopyrimidine. A recent approach by Itoh7 used SuzukieMiyaura
cross-coupling of 2-halo pyrimidines with arylboronic acid. Re-
action of the 4,5-diamino substituents with activated carboxylic
acids ultimately generates the purine core. Direct arylation of pu-
rine derivatives was also performed,8 in particular Pd- assisted
reactions of 2-halo purines,9e11 including Pd-catalyzed cross-
coupling with arylboronic acids.12,13 Recent work by Zhang et al.14
describes the synthesis of 2-aryl-8-oxopurines from a 2-aryl py-
rimidine with a substituted amine and a carboxylic acid in the 4-
and 5-position, respectively. Reaction with diphenylphosphinic
azide followed by Curtius rearrangement leads to the in situ for-
mation of an isocyanate, with subsequent intramolecular
The synthesis of 8-oxopurines also requires a halogen atom at
the 8-position of the purine nucleus and the nucleophilic sub-
stitution is usually performed in aqueous base. The experimental
conditions depend on the nature and position of the ring sub-
stituents, in particular if selectivity is an important issue and other
halogen atoms are present.15
As part of our interest to develop new and simple methods for
the synthesis of purine derivatives,16 we studied the reactivity of
diaminomaleonitrile urea 1, as a simple and easily accessible pre-
cursor of substituted 8-oxopurines.
Previous work on the reaction of compound 1 with aromatic
aldehydes in the presence of base (triethyl amine) resulted in the
formation of 2-aryl-6-carbamoyl purines 3 (Scheme 1).17
In these reactions, imine formation was assisted by intra-
molecular elimination of the water molecule through hydrolysis of
the neighbouring cyano group. Compound 2 was never isolated, as
the basic medium accelerates a cascade intramolecular cyclization
process with formation of the imidazole and pyrimidine rings,
ultimately leading to the 6-carbamoyl purine 3.
2. Results and discussion
In the present work, urea 1 was combined with an aromatic
aldehyde (1.2 M equiv) in acetonitrile, using sulfuric acid catalysis
(Scheme 2). This procedure allowed the isolation of imine de-
rivatives 4 in excellent yield (Table 1), after 5e10 min at room
* Corresponding author. Tel.: þ351 253604379; fax: þ351 253678983; e-mail
address: fproenca@quimica.uminho.pt (M.F. Proenc¸ a).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.11.064

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M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
plausible causes for band duplication. In the 13C NMR, two sets of
bands are also visible for most carbon atoms.
H
Ar
NH2
O
CH2Ph
N
H2N
HN
CN
CN
Attempts to prepare imidazole 5 from the reaction of 617 with 4-
anisaldehyde in the presence of sulfuric acid led to the recovery of
the starting material (6, 86%) after 3 days at room temperature.
Intramolecular cyclization of imidazole 5 to generate the 6-cy-
ano-8-oxopurine 7 is a slow process (7e14 days at room tempera-
ture for the complete consumption of the starting material) but
trifluoroacetic acid catalysis allows a clear evolution to the final
product, which is isolated in excellent yield after 2e10 days (Table 2,
method A). When the same reaction was carried out in the presence
of a large excess of piperidine (5 M equiv) at room temperature,
purine 8 was the major product, isolated after 2e5 days. (Table 2,
method C). The structure assigned to this compound was mainly
based on the NMR data, where correlation techniques (HMBC and
N
N
Ar
ArCHO
O
HN
C N
N
NEt3, EtOH
N
H
O
NH
CH2Ph
O
NH
CH2Ph
O
NH2
3
2
1
Scheme 1. Synthesis of 8-oxo-6-carbamoyl purines 3.
temperature. Intramolecular cyclization between the urea nitrogen
and the nitrile carbon to generate imidazole 5 occurred at room
temperature upon addition of a catalytic amount of DBU to a sus-
pension of compound 4 in acetonitrile (Table 1).
HMQC) unequivocally placed the proton (d 8.3e8.4 ppm) in the 6-
position of purine ring. Purine 8 was also identified in the NMR
spectrum of imidazoles 5, when the solubilization of these com-
pounds in DMSO-d6 was assisted by heating. This observation
inspired a new method for the preparation of these compounds
(Table 2, method B), simply by heating a DMSO suspension of 5, until
the temperature reaches the boiling point of the solution and
keeping this high temperature for 2e3 min.
H
H2N
CN
CN
N
CN
CN
ArCHO
CH3CN
Ar
HN
O
HN
H2SO4, rt
NH
CH2Ph
O
NH
CH2Ph
1
4
Table 2
CH3CN,
DBU, rt
Synthesis of 6-substituted 2-oxopurines 7 and 8
CH3CN, DBU
CH2Ph
CH2Ph
N
Method
N
Ar
N
NH
A, B or C
CH2Ph
NH
CH2Ph
ArCHO
O
H
O
NH
CH3CN
N
N
N
N
N
H
N
H
H
O
O
Ar
X
NH2
N
CN
N
H
N
H
H2SO4, rt
7, X=CN
Ar
5
CN
CN
8, X= H
6
5
Product
Ar
4-H3CC6H4
4-CH3OC6H4
4-NCC6H4
4-HOC6H4
4-BrC6H4
4-FC6H4
X
Methoda
Yield (%)
Scheme 2. Reaction of urea 1 with aldehydes followed by cyclization to oxoimidazole 5.
7a
7b
7c
7d
7e
7f
CN
CN
CN
CN
CN
CN
H
A (7 days)
A (7 days)
A (14 days)
A (10 days)
A (7 days)
A (7 days)
B
C (48 h)
B
C (72 h)
B
C (48 h)
B
C (72 h)
B
C (5 days)
C (5 days)
C (5 days)
85
92
92
52
85
66
78
88
62
75
71
98
57
95
54
63
79
81
Table 1
Isolated yield of products 4 and 5
8a
4-H3CC6H4
Ar
Product
Yield (%)
Product
Yield (%)
8b
8c
8d
8e
4-CH3OC6H4
4-NCC6H4
H
H
H
H
4-H3CeC6H4
4-H3COeC6H4
4-NCeC6H4
4-O2NeC6H4
4-HOeC6H4
4-BreC6H4
4-FeC6H4
4a
4b
4c
4d
4e
4f
91
87
86
86
52
89
96
5a
5b
5c
5d
5e
5f
85
92
86
80
84
91
88
4-O2NC6H4
4-HOC6H4
4g
5g
8f
8g
4-BrC6H4
4-FC6H4
H
H
The structure of imidazole 5 was confirmed by 1H NMR, where
the imine CeH 8.43e8.73 ppm), the imine NeH
9.54e8.76 ppm) and the methylene substituent ( 4.81e4.76 ppm)
a
Reaction conditions for method A: ethanol, TFA (cat.), rt; method B: DMSO,
(d
(d
boiling for 2e3 min; method C: ethanol, piperidine (5 M equiv), rt.
d
were always present as two sets of signals, assigned to distinct
isomeric structures. When the 1H NMR spectrum of a DMSO solu-
The base-catalyzed cyclization of the substituted 2-oxoimida-
zole 5 to generate the 2-aryl-8-oxopurine 8 is a straightforward
method to create this compound family. By comparing with the
approach recently described by Zhang,14 it has the advantage of
milder and less hazardous reaction conditions and the possibility to
incorporate a wide range of aromatic substituents with both elec-
tron-withdrawing and electron-donating groups in the 2-position
of purine ring.
tion of compound 5b (6.7 mg in 600
80 ꢀC, a single set of bands was obtained for all the signals except
for the imine NeH, where two broad singlets ( 9.1e8.8 ppm) were
ml of solvent) was registered at
d
present in a 1:1 ratio. This result supports the assumption that two
conformational isomers are present in solution and the energy of
the molecule overcomes the rotation barrier at
temperature.
a higher
In an attempt to understand the pathway leading either to pu-
rine 7 or 8 from a common precursor 5, the evolution of imidazole
A UV study of a DMSO solution of the same compound, showed
the absence of isosbestic points when the concentration was varied
from 6.96ꢁ10ꢂ4 M to 3.48ꢁ10ꢂ4 M and 1.70ꢁ10ꢂ4 M. This confirms
the presence of a single species in solution, excluding the possibility
of monomeredimer or tautomeric equilibria, other equally
5f (17 mg) in DMSO-d6 solution (600
The spectrum was recorded at intervals over approximately 10 days
and the two singlets at 8.45 and 8.51 ppm (in a 2:1 ratio) for the
m
l) was studied by 1H NMR.
d

M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
757
CeH proton of the imine substituent in 5f was used to quantify this
compound.
Compound 5f, the only component identified when the solution
was prepared, slowlyevolves to the 1,2-dihydropurine 9 (Scheme 3).
The signals for C2eH ( 5.98 ppm,
100
90
80
70
60
50
40
30
20
10
0
5f
9
7e
8f
d
5.76 ppm, J¼6.5 Hz) and N1eH (
d
J¼6.5 Hz) clearly support the cyclic structure of this compound. A
correlation study (HMBC and HMQC) on the NMR solution confirms
that the proton at
Two- and three-bond correlations are visible with CiAr
141.39 ppm), C4 151.14 ppm), C6 98.07 ppm) and CoAr (
d d 68.6 ppm).
5.76 ppm is linked to a sp3 carbon (
(d
(d
(d
d
0
50
100
150
200
t (hours)
128.85 ppm). The NeH proton was localized on N1 considering the
three-bond correlations of this protonwith C5 (
d
119.93 ppm), CiAr (d
141.39 ppm) and the 6-CN group (
d
113.32 ppm).
Fig. 1. 1H NMR study of the evolution of 2-oxoimidazole 5f in DMSO-d6.
CH2Ph
N
PhH2C
8. Addition of acid (TFA) prevents the elimination of HCN from 10
and the equilibrium with its tautomer 9 results in the efficient
consumption of this intermediate through the oxidation process
that leads to the 6-cyanopurine 7. Heating the DMSO solution forces
HCN (gas) to escape and drives the equilibrium to the preferential
formation of purine 8.
H
N
NH
N
Ar
O
O
NH
N
H
N
H
N
H
CN
CN Ar
9
5f
The evolution of imidazole 5 in piperidine was also followed by
1H NMR. In this experiment, imidazole 5b (20 mg) was combined
with 4.5 M equiv of piperidine, in 600
spectrum was registered within the next 5 min and the acidic
proton of the imidazole (a broad singlet at 11.7 ppm) was already
absent. Two different compounds were formed, each of them with
a single set of bands, where the acidic NeH is absent. A plausible
structure for these compounds corresponds to the anion 12, ini-
tially formed and stabilized by intermolecular H-bonding with the
piperidinium cation, that progressively evolves to the anion 13
(Scheme 4). Structure 12 was assigned on the basis of 1H NMR data,
ml of DMSO-d6. The first
-[H2]
N
d
PhH2C
PhH2C
Ar
Ar
N
N
N
H
O
O
N
NH
N
H
N
H
CN
CN
10
7e
-HCN
that shows the imine NeH as a broad singlet at
siderably shielded compared with the starting material 5b (NH at
9.31 and 8.74 ppm). The CeH proton of the imine is not affected
by the formation of the anion (5b, dCH 8.40 and 8.46 ppm, 12 dCH
8.43 ppm), supporting the assumption that the negative charge is
localized in the imidazole ring. After 1 h at room temperature,
compound 12 completely evolves to 13, the major product in so-
lution (94%) where the presence of a small amount of purine 8b
(6%) is already detected.
d 8.3 ppm, con-
PhH2C
PhH2C
Ar
N
Ar
N
d
d
N
N
H
d
O
O
N
N
N
H
N
H
H
8f
11
Scheme 3. Proposed mechanism for the formation of purines 7e and 8f from 2-ox-
oimidazole 5f in DMSO.
H
The methylene protons on N9 are non-equivalent, leading to
slightly different chemical shifts in the NMR spectrum (d 4.63 and
PhH2C
PhH2C
N
NH
N
NH
N
O
4.70 ppm, J¼15.2 Hz). This non-equivalence may result from the
O
N
H
N
H
N
N
H
formation of a tetrahedral stereocenter in the molecule.
H
CN Ar
After 18 h, compound 9 corresponds to approximately 13% of the
reaction mixture, where the starting material 5f is present in a large
excess (ca. 87%) and traces of purines 7e and 8f are already visible.
CN Ar
5b
N H
12
The signal at
quantify this compound and the amount of 6-cyanopurine 7e was
obtained from the signal at 5.10 ppm, corresponding to the
methylene group of the benzyl substituent. A singlet at 6.3 ppm
was assigned to the proton of HCN and the integration of this signal
indicated that the amount of HCN evolved was exactly the same as
the amount of C6-H purine 8f that was formed.
d 8.35 ppm, for the C6-H proton of 8f was used to
H
N
PhH2C
PhH2C
Ar
d
N
N
N
d
O
O
H
H
N
N
Ar
N
N
H
N
NC
10
H
CN H
H
13
The evolution is summarized in Fig. 1, which indicates that after
41 h at room temperature, imidazole 5f cyclized to the dihy-
dropurine 9 in a large extent and this compound was the common
precursor of both purines 7e and 8f. The formation of purine 7e is
the direct result of oxidation of 9 but the formation of purine 8f is
possible through tautomer 10. Compound 10 was not identified in
the reaction mixture, possibly due to the prompt elimination of
HCN to generate 11, a tautomer of purine 8f.
-HCN
Ar
PhH2C
PhH2C
N
N
N
Ar
N
O
O
H
N
N
N
N
H
H
11
H
8b
This experiment indicates that in the absence of external acid or
base, both pathways operate generating mixtures of purines 7 and
Scheme 4. Proposed mechanism for the formation of purine 8b from 2-oxoimidazole
5b in DMSO, in the presence of piperidine.

758
M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
In a separate experiment, intermediate 13 was generated and
confirm that the cyclization reaction is selective, leading exclusively
to 8-oxopurines 7 or 8.
studied by 13C NMR and correlation techniques (HMQC and HMBC),
unequivocally confirming the structure assigned to the imidazole
moiety by comparison with the data previously registered for
Compound 4a was included in a chemical collection of mole-
cules submitted to virtual screening of their biological activity on
a number of protein targets. This structure was identified as a novel
antagonist of all four adenosine receptor subtypes.19 Synthetic ef-
forts are currently focussed on the preparation of a number of
derivatives for in vitro testing of their activity on the adenosine
receptor family.
compound 1418 (Fig. 3, C2
d
166.6 ppm, C4
d 151.9 ppm, C5
d
159.8 ppm). The chemical shift of the carbon atoms in the imid-
azole ring of 13 (C2 d 166.37 ppm, C4 d 153.74 ppm, C5 d 160.50 ppm)
increase by 10e15 ppm compared with the values registered for 5b
(C2
d 153.35 ppm, C4 d 138.78 ppm, C5 d 150.29 ppm). In contrast,
the chemical shift of the carbon atoms of the linear substituent in
the 4-position shifts to lower values. In particular, the chemical
4. Experimental section
4.1. General
shift of the imine carbon in compound 13 (
by approximately 10 ppm units compared with the same carbon
atom in 5b ( 157.71 ppm). This was considered to be due to the
d 148.04 ppm) decreases
d
transfer of the negative charge to this substituent.
All compounds were fully characterized by elemental analysis
and spectroscopic data. The NMR spectra were recorded at
300 MHz for 1H and 75 MHz for 13C or at 400 MHz for 1H and
100 MHz for 13C, including the 1He13C correlation spectra (HMQC
and HMBC). Deuterated DMSO was used as solvent. The chemical
Intramolecular cyclization is a comparatively slow process and
leads to a transient intermediate 10 (not visible in the NMR spec-
trum) that rapidly evolves to the final product 8b through tautomer
11. Elimination of HCN is now assisted by the presence of base
through the formation of piperidinum cyanide, evidenced 1H NMR
spectrum.
The mechanistic proposal presented in Scheme 4 is associated
with the kinetic evolution summarized in Fig. 2. Purine 8b was the
only product in solution after 3 days at room temperature.
shifts are expressed in
d (ppm) and the coupling constants (J) in
Hertz (Hz). IR spectra were recorded on an FT-IR using Nujol mulls
and NaCl cells. The reactions were monitored by thin layer chro-
matography (TLC) using silica gel. The melting points were de-
termined on a melting point apparatus and are uncorrected.
Samples UV/vis absorption spectra were obtained using a quartz
cell with 1 cm path in UV/vis spectrometer (Shimadzu, UV-2501)
controlled by Shimadzu UV Probe 2.00 software.
100
90
80
4.2. General procedure for the synthesis of N-benzyl-N0-(1,2-
dicyano-2-[aryl-methylene]amino vinyl)urea 4
70
12
60
13
50
8b
A catalytic amountof sulfuric acid was added to a suspension of N-
[2-amino-1,2-dicyanovinyl]-N0-benzylurea17 (1, 700 mg, 2.90 mmol)
and the appropriate aldehyde (1.2 M equiv) in acetonitrile (5 mL) and
the reaction mixture was stirred at room temperature. The suspen-
sion was partially solubilized and 5 min later a yellow solid was
formed. Stirring was continued for another 5 min, when the solid was
collectedand washedwith acetonitrileandethanolleadingtothetitle
compounds 4 in pure form.
40
30
20
10
0
0
2
4
6
8
10 12 14 16 18 20 22 24
t (hours)
Fig. 2. 1H NMR study of the evolution of 2-oxoimidazole 5b in DMSO-d6 in the pres-
ence of 5 M equiv of piperidine.
4.2.1. N-Benzyl-N0-(1,2-dicyano-2-{[(4-methylphenyl)
amino}vinyl)urea (4a). Yellow solid (0.91 g, 91%). Mp 230e231 ꢀC;
1H NMR (300 MHz, DMSO-d6):
9.32 (br s, 1H), 8.47 (s, 1H), 7.98 (d,
methylene]
d
J¼8.4 Hz, 2H), 7.90 (t, J¼5.4 Hz, 1H), 7.28e7.39 (m, 7H), 4.35 (d,
PhH2C
J¼5.6 Hz, 2H), 2.38 (s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6):
5
4
NH
1
N
O
2
d
160.8, 151.2, 143.6, 138.7, 132.0, 130.0, 129.6, 128.5, 127.6, 127.2,
N
N
3
118.3, 113.8, 113.2, 112.2, 43.2, 21.4 ppm; IR (Nujol mull):
n 2221,
2212, 1724, 1633, 1578 cmꢂ1. Anal. Calcd for C20H17N5O: C, 69.96; H,
4.99; N, 20.40, found: C, 69.61; H, 5.08; N, 20.29.
N
H2N
4.2.2. N-Benzyl-N0-(1,2-dicyano-2-{[(4-methoxyphenyl) methylene]
amino}vinyl)urea (4b). Yellow solid (0.91 g, 87%). Mp218e219 ꢀC; 1H
14
OMe
NMR (300 MHz, DMSO-d6):
d 9.32 (s, 1H), 8.45 (s, 1H), 8.06 (d,
Fig. 3. Structure of compound 14, reported in previous work.
J¼8.7 Hz, 2H), 7.85 (t, J¼5.7 Hz, 1H), 7.25e7.40 (m, 5H), 7.08 (d,
J¼8.7 Hz, 2H), 4.35 (d, J¼5.7 Hz, 2H), 3.85 (s, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6):163.3,160.4,151.3,138.7,132.1,128.5,127.6,127.4,
3. Conclusion
127.2,117.4,114.6,114.2,113.3,112.3, 55.6, 43.2 ppm; IR (Nujol mull):
n
2221, 2212, 1711, 1660, 1606 cmꢂ1. Anal. Calcd for C20H17N5O2: C,
66.84; H, 4.77; N, 19.49, found: C, 66.82; H, 4.91; N, 19.41.
A simple and efficient method was developed for the synthesis
of 2-aryl-6-cyano and 6-unsubstituted 8-oxopurines. The reaction
occurs from a common 2-oxoimidazole precursor that evolves to
the 6-cyanopurine in the presence of acid (TFA) or to the 6-
unsubstituted analogue in the presence of base (piperidine) or
upon heating in DMSO. These products were isolated in a high
purity form by simple filtration. Both compounds are difficult to
prepare by the synthetic methods currently available. Mechanistic
studies performed by 1H NMR on the evolution of 2-oxoimidazole 5
4.2.3. N-Benzyl-N0-(1,2-dicyano-2-{[(4-cyanophenyl)
amino}vinyl)urea (4c). Yellow solid (0.89 g, 86%). Mp 215e216 ꢀC;
1H NMR (400 MHz, DMSO-d6):
9.59 (s, 1H), 8.60 (s, 1H), 8.25 (d,
methylene]
d
J¼8.4 Hz, 2H), 8.00 (d, J¼8.4 Hz, 2H), 7.87 (t, J¼5.6 Hz, 1H),
7.27e7.39 (m, 5H), 4.36 (d, J¼4.2 Hz, 2H) ppm; 13C NMR (100 MHz,
DMSO-d6):
d 159.1, 151.0, 138.6, 138.4, 132.8, 130.1, 128.5, 127.6,

M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
759
127.3, 120.2, 118.4, 114.3, 112.9, 112.88, 112.0, 43.2; IR (Nujol mull):
n
2.37 (s, 3H, AþB) ppm; 13C NMR (75 MHz, DMSO-d6):
d
159.3 (B),
2228, 2213, 1706, 1663, 1604 cmꢂ1
.
Anal. Calcd for
158.2 (A), 154.0 (B); 153.4 (A), 150.3 (A), 142.7 (B), 142.3 (A), 139.4
(A), 136.6 (B), 136.3 (A), 132.9 (A), 132.7 (B), 129.7 (B), 129.6 (AþB),
129.4 (A), 128.6 (A), 128.5 (B), 127.5 (B), 127.4 (A), 127.1 (AþB), 113.3
(B), 112.1 (A), 98.84 (AþB), 41.8 (B), 40.9 (A), 21.3 (AþB) ppm; IR
C20H14N6O$0.2H2O: C, 67.10; H, 4.06; N, 23.48, found: C, 66.89; H,
4.02; N, 23.41.
4.2.4. N-Benzyl-N0-(1,2-dicyano-2-{[(4-nitrophenyl) methylene]amino}
(Nujol mull): n
2205, 1742, 1632, 1591 cmꢂ1. Anal. Calcd for
C20H17N5O$0.1H2O: C, 69.59; H, 5.02; N, 20.29, found: C, 69.47; H,
vinyl)urea (4d). Orange solid (0.93 g, 86%). Mp 207e208 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
9.66 (s, 1H), 8.65 (s, 1H), 8.33 (s, 5H), 7.89 (t,
5.13; N, 20.33.
J¼5.7 Hz, 1H), 7.27e7.40 (m, 5H), 4.37 (d, J¼5.7 Hz, 2H) ppm; 13C
NMR (75 MHz, DMSO-d6):
d
158.7, 151.0, 149.4, 140.1, 138.6, 130.7,
4.3.2. 2(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-me-
thoxyphenyl)methylene]amino} acetonitrile (5b). The title com-
pound was prepared following the general procedure, and was
isolated after stirring the reaction mixture at room temperature for
15 min. Yellow solid (0.66 g, 92%). Mp 231e232 ꢀC; imidazole 5b
was present in the NMR spectra as two isomeric forms A, B in
128.5, 127.6, 127.3, 124.0, 120.5, 112.90, 112.89, 112.0, 43.2; IR (Nujol
mull): Anal. Calcd for
n
2224, 2214, 1708, 1660, 1604 cmꢂ1
.
C19H14N6O3: C, 60.96; H, 3.77; N, 22.45, found: C, 60.60; H, 3.91; N,
22.34.
4.2.5. N-Benzyl-N0-(1,2-dicyano-2-{[(4-hydroxyphenyl) methylene]
a 1.6:1 ratio. 1H NMR (400 MHz, DMSO-d6):
d
11.68 (br s, 1H, AþB),
amino}vinyl)urea (4e). Red solid (0.53 g, 52%). Mp 187e188 ꢀC; 1H
9.30 (s, 1H, A), 8.75 (s, 1H, B), 8.46 (s, 1H, B), 8.41 (s, 1H, A), 8.10 (d,
J¼8.8 Hz, 2H, AþB), 7.25e7.37 (m, 5H, AþB), 7.04 (d, J¼8.8 Hz, 2H,
AþB), 4.80 (s, 2H, A), 4.75 (s, 2H, B), 3.84 (s, 3H, AþB) ppm; 13C NMR
NMR (400 MHz, DMSO-d6):
d 9.78 (br s, 2H), 8.38 (s, 1H), 7.94 (d,
J¼8.8 Hz, 2H), 7.85 (t, J¼5.6 Hz, 1H), 7.26e7.38 (m, 5H), 6.89 (d,
J¼8.8 Hz, 2H), 4.34 (d, J¼5.6 Hz, 2H) ppm; 13C NMR (100 MHz,
(100 MHz, DMSO-d6):
d 162.6 (B); 162.5 (A), 158.5 (B), 157.7 (A),
DMSO-d6):
d
162.5, 160.5, 151.4, 138.8, 132.5, 128.5, 127.5, 127.2,
154.2 (B), 153.4 (A), 150.2 (A), 138.8 (AþB), 136.7 (B), 136.3 (A), 131.6
(B), 131.5 (A), 128.6 (A), 128.4 (B), 128.3 (A), 128.2 (B), 127.4 (B),
127.3 (B), 127.2 (B), 127.1 (A), 114.3 (B), 114.26 (A), 113.6 (B), 112.2
(A), 99.4 (B), 99.0 (A), 55.5 (AþB), 41.7 (B), 40.8 (A) ppm; IR (Nujol
125.9, 116.9, 116.0, 114.5, 113.4, 112.3, 43.1 ppm; IR (Nujol mull):
n
2228, 1709, 1661, 1604 cmꢂ1. Anal. Calcd for C19H15N5O2$H2O: C,
62.80; H, 4.72; N, 19.27, found: C, 62.85; H, 4.58; N, 19.05.
mull): n
2201, 1736, 1631 cmꢂ1. Anal. Calcd for C20H17N5O2$0.1H2O:
4.2.6. N-Benzyl-N0-(1,2-dicyano-2-{[(4-bromophenyl)methyl-ene]
C, 66.50; H, 4.80; N, 19.39, found: C, 66.32; H, 4.85; N, 19.33.
amino}vinyl)urea (4f). Red solid (1.05 g, 89%). Mp 228e229 ꢀC; 1H
NMR (400 MHz, DMSO-d6):
d
9.48 (s, 1H), 8.51 (s, 1H), 8.03 (d,
4.3.3. 2(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-cyano-
phenyl)methylene]amino}acetonitrile (5c). The title compound was
prepared following the general procedure, and was isolated after
stirring the reaction mixture at room temperature for 1 h. Yellow
solid (0.61 g, 85%). Mp 304e305 ꢀC; imidazole 5c was present in the
NMR spectra as two isomeric forms A, B in a 2.3:1 ratio. 1H NMR
J¼8.4 Hz, 2H), 7.87 (t, J¼5.6 Hz, 1H), 7.75 (d, J¼8.4 Hz, 2H),
7.27e7.39 (m, 5H), 4.37 (d, J¼4.2 Hz, 2H) ppm; 13C NMR (100 MHz,
DMSO-d6):
d 159.8, 151.1, 138.6, 133.8, 132.0, 131.5, 128.5, 127.6,
127.2, 126.8, 119.1, 113.3, 113.0, 112.1, 43.2 ppm; IR (Nujol mull):
n
2225, 2215, 1659, 1606 cmꢂ1. Anal. Calcd for C19H14N5BrO:
55.90; H, 3.46; N, 17.15, found: C, 56.28; H, 3.75; N, 17.48.
n
C,
(400 MHz, DMSO-d6):
d
11.96 (br s, 1H, AþB), 9.54 (s, 1H, A), 8.90 (s,
1H, B), 8.59 (s, 1H, B), 8.53 (s, 1H, A), 8.35 (d, J¼8.4 Hz, 2H, AþB),
4.2.7. N-Benzyl-N0-(1,2-dicyano-2-{[(4-fluorophenyl)
amino}vinyl)urea (4g). Red solid (0.96 g, 96%). Mp 222e223 ꢀC; 1H
NMR (300 MHz, DMSO-d6): 9.44 (s, 1H), 8.52 (s, 1H), 8.17 (dd,
methylene]
7.96 (d, J¼8.4 Hz, 2H, AþB), 7.26e7.37 (m, 5H, AþB), 4.81 (s, 2H, A),
4.76 (s, 2H, B) ppm; 13C NMR (100 MHz, DMSO-d6):
d 157.4 (B),
d
156.3 (A), 153.9 (B), 153.3 (A), 150.1 (A), 141.4 (AþB), 139.3 (A), 139.2
(B), 136.5 (B), 136.2 (A), 132.6 (AþB), 129.9 (AþB), 128.6 (A), 128.4
(B), 127.44 (A), 127.40 (B), 127.1 (A), 118.6 (AþB), 113.5(B) 113.4 (A),
113.3 (B) 111.9 (A), 98.1 (AþB), 41.8 (B), 41.0 (A) ppm; IR (Nujol
J¼8.7 , 5.4 Hz, 2H), 7.85 (t, J¼5.4 Hz, 1H), 7.28e7.42 (m, 7H), 4.36 (d,
J¼5.7 Hz, 2H) ppm; 13C NMR (75 MHz, DMSO-d6)
d 164.9
(J¼250.88 Hz), 159.7, 151.2, 138.7, 132.5 (d, J¼9.15 Hz), 131.4 (d,
J¼2.85 Hz), 128.5, 127.6, 127.3, 118.8, 116.2 (J¼21.98 Hz), 113.5, 113.1,
mull):
n
2229, 2217, 1735, 1635 cmꢂ1. Anal. Calcd for C20H14N6O: C,
112.2, 43.2 ppm; IR (Nujol mull):
n
2223, 1709, 1658, 1611,
67.79; H, 3.98; N, 23.72, found: C, 67.67; H, 4.08; N, 23.94.
1604 cmꢂ1. Anal. Calcd for C19H14N5FO: C, 65.70; H, 4.06; N, 20.16,
found: C, 65.36; H, 4.27; N, 20.56.
4.3.4. 2(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-nitro-
phenyl)methylene]amino}acetonitrile (5d). The title compound was
prepared following the general procedure, and was isolated after
stirring the reaction mixture at room temperature for 10 min. Yel-
low solid (0.60 g, 80%). Mp 289e300 ꢀC; imidazole 5d was present
in the NMR spectra as two isomeric forms A, B in a 1.7:1 ratio. 1H
4.3. General procedure for the synthesis of (1-benzyl-5-imino-
2-oxoimidazolidin-4-ylidene){[(1)arylmethylene]-amino}
acetonitrile 5
A catalytic amount of DBU was added to a suspension of N-
NMR (300 MHz, DMSO-d6): d 9.50 (s, 1H, A), 8.73 (s, 1H, B), 8.66 (s,
benzyl-N0-(1,2-dicyano-2-[aryl-methylene]amino}vinyl)urea
(4,
1H, B), 8.57 (s, 1H, A), 8.40 (d, J¼8.7 Hz, 2H, A), 8.29 (d, J¼9.3 Hz, 2H,
AþB and 2H, B), 7.25e7.35 (m, 5H, AþB), 4.80 (d, 2H, A), 4.72 (d, 2H,
B) ppm; evolution in the NMR tube, with formation of both 6-
unsubstituted purine and 6-cyanopurine prevents the identifica-
tion of the 13C NMR signals for the 2-oxoimidazole; IR (Nujol mull):
2.00 mmol) in acetonitrile (5 mL) and the mixture was stirred at
room temperature for 10 mine1 h. The yellow solid was filtered
and washed with acetonitrile and diethyl ether. This procedure was
used to prepare compounds 5.
n
2214, 1737, 1634 cmꢂ1. Anal. Calcd for C19H14N6O3$0.1H2O: C,
4.3.1. 2-(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-meth-
ylphenyl)methylene]amino} acetonitrile (5a). The title compound
was prepared following the general procedure, and was isolated
after stirring the reaction mixture at room temperature for 30 min.
Yellow solid (0.59 g, 85%). Mp 228e229 ꢀC; imidazole 5a was
present in the NMR spectra as two isomeric forms A, B in a 1.8:1
60.67; H, 3.81; N, 22.34, found: C, 60.59; H, 3.96; N, 21.99.
4.3.5. 2(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-hydrox-
yphenyl)methylene]amino} acetonitrile (5e). The title compound
was prepared following the general procedure, and was isolated
after stirring the reaction mixture at room temperature for 20 min.
Yellow solid (0.58 g, 82%). Mp 229e230 ꢀC; imidazole 5e was
present in the NMR spectra as two isomeric forms A, B a 1.5:1 ratio.
ratio. 1H NMR (300 MHz, DMSO-d6):
d
11.72 (br s, 1H, AþB), 9.36 (s,
1H, A), 8.80 (s,1H, B), 8.48 (s,1H, B), 8.43 (s,1H, A), 8.04 (d, J¼8.1 Hz,
2H, AþB), 7.20e7.40 (m, 7H, AþB), 4.80 (s, 2H, A), 4.76 (s, 2H, B),
1H NMR (400 MHz, DMSO-d6):
d
11.08 (br s, 1H, AþB), 9.24 (s, 1H,

760
M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
A), 8.69 (s,1H, B), 8.39 (s,1H, B), 8.35 (s,1H, A), 7.98 (d, J¼8.4 Hz, 2H,
AþB), 7.25e7.37 (m, 5H, AþB), 6.85 (d, J¼8.4 Hz, 2H, AþB), 4.79 (s,
was filtered and washed with diethyl ether. This method was used to
prepare compounds 8.
2H, A), 4.74 (s, 2H, B) ppm; 13C NMR (100 MHz, DMSO-d6):
d 161.6
(B), 161.4 (A) 158.3 (B), 157.9 (A), 154.7 (B),153.4 (A),150.4 (A),136.9
(B), 136.3 (A), 131.8 (AþB), 128.6 (A), 128.4 (B), 127.4 (B), 127.3 (A),
127.2 (B), 127.1 (A), 126.9 (B), 115.7 (AþB), 114.0 (B), 112.3 (A), 99.2
4.4.1. 9-Benzyl-2-(4-methylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-
carbonitrile (7a). The title compound was prepared following
method A and the reaction mixture was stirred at room temperature
for 7 days. Off-white solid (0.09 g, 85%). Mp 265e266 ꢀC; 1H NMR
(AþB), 41.7 (B), 40.8 (A) ppm; IR (Nujol mull):
n 2215, 1736,
1637 cmꢂ1. Anal. Calcd for C19H15N5O2$0.5H2O: C, 64.40; H, 4.55,
found: C, 64.07; H, 4.72.
(300 MHz, DMSO-d6):
d
12.55 (brs,1H), 8.14 (d, J¼8.1 Hz, 2H), 7.43 (d,
J¼7.2 Hz, 2H), 7.25e7.36 (m, 5H), 5.08 (s, 2H), 2.35 (s, 3H) ppm; 13C
NMR (75 MHz, DMSO-d6):
d 156.1, 152.9, 152.2, 140.2, 135.7, 133.4,
4.3.6. 2(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-bromo-
phenyl)methylene]amino} acetonitrile (5f). The title compound was
prepared following the general procedure, and was isolated after
stirringthe reaction mixtureat roomtemperaturefor 20 min. Yellow
solid (0.74 g, 91%). Mp 265e266 ꢀC; imidazole 5f was present in the
NMR spectra as two isomeric forms A, B in a 2:1 ratio. 1H NMR
129.0, 128.4,127.7, 127.5, 127.0, 124.3, 114.3,113.6, 42.9, 20.7 ppm; IR
(Nujol mull):
n
2239, 1725, 1631, 1601 cmꢂ1. Anal. Calcd for
C20H15N5O$0.75H2O: C, 67.69; H, 4.69, found: C, 68.03; H, 4.89.
4.4.2. 9-Benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-
6-carbonitrile (7b). The title compound was prepared following
method A, and the reaction mixture was stirred at room tempera-
ture for 7 days. Off-white solid (0.10 g, 92%). Mp 277e278 ꢀC; 1H
(400 MHz, DMSO-d6):
d
11.85 (br s, 1H, AþB), 9.44 (s, 1H, A), 8.85 (s,
1H, B), 8.51 (s,1H, B), 8.45 (s,1H, A), 8.11 (d, J¼8.4 Hz, 2H, AþB), 7.70
(d, J¼8.4 Hz, 2H, AþB), 7.26e7.37 (m, 5H, AþB), 4.80 (s, 2H, A), 4.76
NMR (300 MHz, DMSO-d6):
7.42 (d, J¼6.6 Hz, 2H), 7.25e7.37 (m, 3H), 7.03 (d, J¼8.7 Hz, 2H), 5.06
(s, 2H), 3.80 (s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6):
161.3,
156.1,153.2, 152.3, 135.9, 128.9, 128.7, 128.6, 127.9,127.8, 124.1, 114.6,
d
12.62 (br s, 1H), 8.19 (d, J¼8.7 Hz, 2H),
(s, 2H, B) ppm; 13C NMR (100 MHz, DMSO-d6):
d 158.1 (B), 157.0 (A),
153.8 (B),153.3 (A),150.2 (A),140.0 (AþB),136.6 (B),136.2 (A),134.6
(A), 134.5 (B), 131.79 (B), 131.75 (A), 131.31 (B), 131.26 (A), 128.6 (A),
128.4 (B), 127.43 (B), 127.35 (B), 127.3 (A), 127.1 (A), 126.0 (B), 125.6
(A), 113.2 (B), 112.0 (A), 99.0 (B), 98.4 (A), 41.8 (B), 40.9 (A) ppm; IR
d
114.0, 113.7, 55.3, 43.0 ppm; IR (Nujol mull):
n 1725, 1631,
1600 cmꢂ1. Anal. Calcd for C20H15N5O2$0.3H2O: C, 66.22; H, 4.33,
(Nujol mull):
n
2215, 1735,1634 cmꢂ1. Anal. Calcd for C19H14N5 Br O:
found: C, 66.55; H, 4.71.
C, 55.90; H, 3.46; N, 17.15, found: C, 55.93; H, 3.60; N, 17.22.
4.4.3. 9-Benzyl-2-(4-cyanophenyl)-8-oxo-8,9-dihydro-7H-purine-6-
carbonitrile (7c). The title compound (7c) was prepared following
method A, and the reaction mixture was stirred at room tempera-
ture for 14 days. The yellow suspension evolved to a white sus-
pension and the solid was filtered and washed by diethyl ether and
ethanol. Off-white solid (0.10 g, 93%). Mp >350 ꢀC; 1H NMR
4.3.7. 2(1-Benzyl-5-imino-2-oxoimidazolidin-4-ylidene){[(4-fluo-
rophenyl)methylene]amino}acetonitrile (5g). The title compound
was prepared following the general procedure, and was isolated
after stirring the reaction mixture at room temperature for 10 min.
Yellow solid (0.61 g, 88%). Mp 239e240 ꢀC; imidazole 5g was
present in the NMR spectra as two isomeric forms A, B in a 1.9:1
(300 MHz, DMSO-d6):
(d, J¼8.4 Hz, 2H), 7.43 (d, J¼6.6 Hz, 2H), 7.27e7.37 (m, 3H), 5.10 (s,
2H) ppm; 13C NMR (75 MHz, DMSO-d6):
154.0, 153.2, 152.5, 140.2,
135.7, 132.8, 128.6, 127.9, 127.8, 125.7, 118.6, 114.3, 113.6, 112.7,
43.1 ppm; IR (Nujol mull):
2229, 2227, 1726, 1632, 1604 cmꢂ1
d
12.88 (br s, 1H), 8.40 (d, J¼8.4 Hz, 2H), 7.93
ratio. 1H NMR (300 MHz, DMSO-d6):
d
11.79 (br s, 1H, AþB), 9.41 (s,
1H, A), 8.83 (s, 1H, B), 8.57 (s, 1H, B), 8.47 (s, 1H, A), 8.26 (s, 1H, A),
8.23 (dd, J¼8.5 , 5.8 Hz, 2H, AþB), 7.24e7.40 (m, 7H, AþB), 4.80 (s,
d
2H, A), 4.76 (s, 2H, B) ppm; 13C NMR (75 MHz, DMSO-d6):
d
164.5
n
.
(J¼250.27 Hz, B), 164.4 (J¼249.07 Hz, A), 158.1 (B), 157.0 (A), 153.9
(B), 153.7 (B), 153.4 (A), 150.2 (A), 139.9 (A), 136.6 (B), 136.3 (A),
132.1(J¼10.87 Hz, B), 132.0 (J¼8.55 Hz, A), 128.6 (A), 128.5 (B), 127.5
(A), 127.4 (B), 127.3 (B), 127.1 (A), 115.9 (J¼21.75 Hz, AþB), 113.2 (B),
Anal. Calcd for C20H12N6O$0.5H2O: C, 66.48; H, 3.63; N, 23.26,
found: C, 66.86; H, 3.71; N, 22.87.
4.4.4. 9-Benzyl-2-(4-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-
6-carbonitrile (7d). The title compound was prepared following
method A, and the reaction mixture was stirred at room tempera-
ture for 10 days. Off-white solid (0.06 g, 52%). Mp 325e326 ꢀC; 1H
112.1 (A), 99.2 (B), 98.5 (A), 41.8 (B), 40.9 (A) ppm; IR (Nujol mull):
n
2213,1735,1635 cmꢂ1. Anal. Calcd for C19H14N5FO: C, 65.70; H, 4.06;
N, 20.16, found: C, 65.60; H, 4.10; N, 20.40.
NMR (300 MHz, DMSO-d6):
J¼8.4 Hz, 2H), 7.20e7.45 (m, 5H), 6.85 (d, J¼8.4 Hz, 2H), 5.06 (s, 2H)
ppm; 13C NMR (75 MHz, DMSO-d6):
159.9, 156.5, 153.2, 152.3,
136.0, 129.1, 128.6, 127.8, 127.7, 127.2, 123.9, 115.5, 114.6, 113.7,
42.9 ppm; IR (Nujol mull):
2254, 2222, 1719, 1633 cmꢂ1. Anal.
d 12.60 (br s, 1H), 9.96 (s, 1H), 8.13 (d,
4.4. General procedure for the synthesis of 2-aryl-6-cyano-8-
oxopurines 7 and 2-aryl-8-oxopurines 8
d
Method A: A suspension of (1-benzyl-5-imino-2-oxoimidazolidin-
4-ylidene){[(1)arylmethylene]-amino}acetonitrile (5, 0.30 mmol) in
ethanol (100 mL) with a catalytic amount of trifluoroacetic acid was
stirred at room temperature for 7e14 days. The solvent was removed
under reduced pressure and addition of diethyl ether led to a solid
precipitate that was filtered and washed with diethyl ether. This
procedure was used to prepare compounds 7.
Method B: A suspension of (1-benzyl-5-imino-2-oxoimidazolidin-
4-ylidene){[(1)arylmethylene]-amino}acetonitrile (5, 0.30 mmol) in
dimethylsulfoxide (3 mL) was heated under reflux for 2e3 min. The
solution was cooled and poured onto water (25 mL). The off-white
solid precipitate was filtered and washed with water. This method
was used to prepare compounds 8.
n
Calcd for C19H13N5O2$1.1H2O: C, 62.84; H, 4.22; N, 19.28, found: C,
63.15; H, 4.09; N, 18.90.
4.4.5. 9-Benzyl-2-(4-bromophenyl)-8-oxo-8,9-dihydro-7H-purine-6-
carbonitrile (7e). Thetitlecompound wasprepared following method
A,andthereactionmixturewasstirredatroomtemperaturefor7days.
Off-white solid (0.10 g, 85%). Mp 321e322 ꢀC; 1H NMR (300 MHz,
DMSO-d6):
d
12.67 (br s, 1H), 8.21 (d, J¼8.4 Hz, 2H), 7.69 (d, J¼8.4 Hz,
2H), 7.42 (d, J¼6.9 Hz,2H), 7.25e7.37 (m, 3H), 5.1 (s, 2H) ppm; 13CNMR
(75 MHz, DMSO-d6):
d 155.0, 153.0, 152.3, 135.5, 135.3, 131.5, 129.0,
128.3,127.6,127.5,124.9,124.0,114.1,113.5, 42.9 ppm;IR (Nujolmull):
n
2238, 1725,1629,1600 cmꢂ1. Anal. Calcd for C19H12N5BrO: C, 56.18; H,
2.97; N, 17.23, found: C, 56.12; H, 3.14; N, 17.33.
Method C: A suspension of (1-benzyl-5-imino-2-oxoimidazolidin-
4-ylidene){[(1)arylmethylene]-amino}acetonitrile (5, 0.30 mmol)
and piperidine (5 M equiv) in ethanol (100 mL) was stirred at room
temperature for 2e5 days. The solvent was removed under reduced
pressure and addition of diethyl ether led to a solid precipitate that
4.4.6. 9-Benzyl-2-(4-fluorophenyl)-8-oxo-8,9-dihydro-7H-purine-6-
carbonitrile (7f). The title compound was prepared following
method A, and the reaction mixture was stirred at room

M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
761
temperature for
334e335 ꢀC; 1H NMR (300 MHz, DMSO-d6):
(dd, J¼9.0 , 5.4 Hz, 2H), 7.43 (d, J¼6.9 Hz, 2H), 7.25e7.37 (m, 5H),
5.08 (s, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
163.7
7
days. Off-white solid (0.07 g, 66%). Mp
5.05 (s, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
159.3, 156.5,
d
12.73 (br s, 1H), 8.29
153.3, 150.3, 136.7, 133.3, 128.8, 128.73, 128.68, 127.8, 127.6, 119.8,
115.3, 42.5 ppm; IR (Nujol mull):
n
1717, 1627, 1603 cmꢂ1. Anal.
d
Calcd for C18H14N4O2$1.4H2O. 0.2 DMSO: C, 61.53; H, 4.88; N, 15.60,
(J¼246.83 Hz), 155.1, 153.1, 152.4, 135.8, 132.6 (J¼2.85 Hz), 129.5
found: C, 61.50; H, 4.60; N, 15.39.
(J¼8.85 Hz), 128.6, 127.9, 127.8, 124.7, 115.6 (J¼21.68 Hz), 114.4,
113.6, 43.1 ppm; IR (Nujol mull):
n
2236, 1725, 1634, 1602 cmꢂ1
.
4.4.12. 9-Benzyl-2-(4-bromophenyl)-7,9-dihydro-8H-purin-8-one
(8f). The title compound was prepared following method C (0.09 g,
79%), by stirring the reaction mixture at room temperature for 5
days. Off-white solid, mp 331e332 ꢀC; 1H NMR (300 MHz, DMSO-
Anal. Calcd for C19H12N5FO: C, 66.08; H, 3.50; N, 20.28, found: C,
66.15; H, 3.42; N, 20.56.
4.4.7. 9-Benzyl-2-(4-methylphenyl)-7,9-dihydro-8H-purin-8-one
(8a). The title compound was prepared following method B
(0.075 g, 78%) and following method C (0.08 g, 88%), by stirring the
reaction mixture at room temperature for 48 h. Off-white solid, mp
d6):
d
11.56 (br s, 1H), 8.34 (s, 1H), 8.25 (d, J¼8.7 Hz, 2H), 7.66 (d,
J¼8.7 Hz, 2H), 7.40 (d, J¼7.2 Hz, 3H), 7.33 (t, J¼7.2 Hz, 2H), 7.28 (t,
J¼7.2 Hz, 1H), 5.07 (s, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
155.0, 153.2, 150.3, 136.8, 136.5, 133.2, 131.6, 129.0, 128.6, 127.8,
303e304 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
11.48 (br s,1H), 8.31 (s,
127.6, 123.5, 120.9, 42.5 ppm; IR (Nujol mull): n 1719, 1622,
1H), 8.20 (d, J¼8.4 Hz, 2H), 7.40 (d, J¼7.2 Hz, 2H), 7.32 (t, J¼7.5 Hz,
1600 cmꢂ1. Anal. Calcd for C18H13N4BrO: C, 56.71; H, 3.44; N, 14.70,
found: C, 56.64; H, 3.54; N, 14.79.
3H), 7.25 (d, J¼8.4 Hz, 2H), 5.1 (s, 2H), 2.33 (s, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6):
d 156.2, 153.4, 150.3, 139.5, 136.7, 135.0, 133.3,
128.7, 127.91, 127.9, 127.7, 127.1, 120.5, 42.6, 21.0 ppm; IR (Nujol
4.4.13. 9-Benzyl-2-(4-fluorophenyl)-7,9-dihydro-8H-purin-8-one
(8g). The title compound was prepared following method C (0.08 g,
83%), by stirring the reaction mixture at room temperature for 5
days. Off-white solid, mp 292e293 ꢀC; 1H NMR (300 MHz, DMSO-
mull):
n
1721,1623,1603 cmꢂ1. Anal. Calcd for C19H16N4O$0.2H2O: C,
71.32; H, 5.17; N, 17.51, found: C, 71.20; H, 5.38; N, 17.57.
4.4.8. 9-Benzyl-2-(4-methoxyphenyl)-7,9-dihydro-8H-purin-8-one
d6):
d
8.35 (dd, J¼9.0 , 5.7 Hz, 2H), 8.33 (s, 1H), 7.25e7.45 (m, 7H),
(8b). The title compound was prepared following method
B
5.07(s, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
163.3
(0.06 mg, 62%) and using method C (0.075 g, 75%), by stirring the
reaction mixture at room temperature for 72 h. Off-white solid, mp
(J¼245.48 Hz), 155.4, 153.4, 150.4, 136.6, 134.1 (J¼2.93 Hz), 133.2,
129.3 (J¼8.55 Hz), 128.6, 127.8, 127.6, 120.9, 115.4 (J¼21.45 Hz),
263e264 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
11.42 (br s,1H), 8.28 (s,
42.5 ppm; IR (Nujol mull): n
1722, 1623, 1610 cmꢂ1. Anal. Calcd for
1H), 8.26(d, J¼8.7 Hz, 2H), 7.39(d, J¼6.9 Hz, 2H), 7.32 (t, J¼6.9 Hz, 2H),
C18H13N4FO$0.6H2O: C, 65.29; H, 4.32; N, 16.92, found: C, 65.65; H,
4.28; N, 17.01.
7.28 (t, J¼6.9 Hz 1H), 7.00 (d, J¼8.7 Hz, 2H), 5.06 (s, 2H), 3.80 (s, 3H)
ppm; 13C NMR (75 MHz, DMSO-d6):
d 160.7, 156.1, 153.3, 150.3, 136.6,
133.2,130.2,128.63,128.61,127.8,127.6,120.0,113.9, 55.2, 42.5 ppm;IR
Acknowledgements
(Nujol mull): Anal. Calcd for
n
1716, 1623, 1601 cmꢂ1
.
C19H16N4O2$0.2H2O: C, 67.93; H, 4.92; N, 16.68, found: C, 67.66; H,
4.79; N, 16.97.
The authors gratefully acknowledge the financial support by the
ˇ
~
University of Minho and Fundac¸ ao para a Ciencia e Tecnologia and
a post-doc grant awarded to Dr. M.Z. (SFRH/BPD/27029/2006).
4.4.9. 9-Benzyl-2-(4-cyanophenyl)-7,9-dihydro-8H-purin-8-one
(8c). The title compound was prepared following method B (0.07 g,
71%) and using method C (0.10 g, 98%), by stirring the reaction
mixture at room temperature for 48 h. Off-white solid, mp
Supplementary data
273e274 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d 11.57 (br s,1H), 8.45 (d,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.11.064. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
J¼8.4 Hz, 2H), 8.38 (s, 1H), 7.91 (d, J¼8.7 Hz, 2H), 7.40 (d, J¼7.5 Hz,
2H), 7.33 (t, J¼7.5 Hz, 2H), 7.28 (t, J¼7.5 Hz 1H), 5.08 (s, 2H) ppm; 13C
NMR (75 MHz, DMSO-d6):
d 154.0, 153.3, 150.3, 141.7, 136.4, 133.2,
132.6,128.6,127.8,127.7,127.6,121.4,118.8,112.0, 42.6 ppm; IR (Nujol
mull):
n
2228, 1725, 1619, 1607 cmꢂ1. Anal. Calcd for C19H13N5O: C,
69.71; H, 4.00; N, 21.39, found: C, 69.45; H, 4.18; N, 21.52.
References and notes
1. (a) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987e4006; (b)
Collins, I.; Caldwell, J. J. Bicyclic 5e6 Systems: Purines, Comprehensive Hetero-
cyclic Chemistry III; Elsevier: Oxford, UK, 2008, Chapter 10.11, pp 525e597; (c)
Legraverend, M. Tetrahedron 2008, 64, 8585e8603.
4.4.10. 9-Benzyl-2-(4-nitrophenyl)-7,9-dihydro-8H-purin-8-one
(8d). The title compound was prepared following method B (0.06 g,
57%) and using method C (0.10 mg, 95%), by stirring the reaction
mixture at room temperature for 72 h. Off-white solid, mp
2. Hirota, K.; Kazaoka, K.; Niimoto, I.; Kumihara, H.; Sajiki, H.; Isobe, Y.; Takaku, H.;
Tobe, M.; Ogita, H.; Ogino, T.; Ichii, S.; Kurimoto, A.; Kawakami, H. J. Med. Chem.
2002, 45, 5419e5422.
346e347 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d 11.59 (br s, 1H), 8.52
ꢀ
(d, J¼9.0 Hz, 2H), 8.40 (s,1H), 8.29 (d, J¼9.0 Hz, 2H), 7.42 (d, J¼7.5 Hz,
3. Bourguignon, J.-J.; Desaubry, L.; Raboisson, P.; Wermuth, C.-G.; Lugnier, C.
2H), 7.34 (t, J¼7.5 Hz, 2H), 7.27 (t, J¼7.5 Hz,1H) 5.09 (s, 2H) ppm; 13C
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4. Chapman, E.; Ding, S.; Schultz, P. G.; Wong, C.-H. J. Am. Chem. Soc. 2002, 124,
14524e14525.
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A. Eur. J. Med. Chem. 2003, 38, 983e990; (b) Giorgi, I.; Bianucci, A. M.; Biagi,
G.; Livi, O.; Scartoni, V.; Leonardi, M.; Pietra, D.; Coi, A.; Massarelli, I.; Nofal,
F. A.; Fiamingo, F. L.; Anastasi, P.; Giannini, G. Eur. J. Med. Chem. 2007,
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NMR (75 MHz, DMSO-d6):
d 153.7, 153.3, 150.4, 148.1, 143.4, 136.4,
133.2, 128.6, 128.0, 127.8, 127.7, 123.8, 121.6, 42.7; IR (Nujol mull):
n
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H, 3.85; N, 19.96, found: C, 61.56; H, 3.71; N, 19.90.
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(8e). The title compound was prepared following method B (0.06 g,
54%) and using method C (0.07 mg, 63%), by stirring the reaction
mixture at room temperature for 5 days. Off-white solid, mp
307e308 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d 11.38 (br s, 1H), 9.84
(br s, 1H), 8.26 (s,1H), 8.17 (d, J¼8.7 Hz, 2H), 7.39 (d, J¼6.9 Hz, 2H),
7.33 (t, J¼6.9 Hz, 2H), 7.25 (t, J¼6.9 Hz, 1H), 6.84 (d, J¼8.7 Hz, 2H),

762
M.E.A. Zaki, M.F. Proenc¸ a / Tetrahedron 67 (2011) 755e762
ꢀ
~
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