Synthesis of novel 6-enaminopurines

Article abstract of DOI:10.1039/b406806h

Two different approaches have been used for the synthesis of 6-enaminopurines 6 from 5-amino-4-cyanoformimidoyl imidazoles 1. In the first approach imidazoles 1 were reacted with ethoxymethylenemalononitrile or ethoxymethylenecyanoacetate under mild exper

Full text of DOI:10.1039/b406806h

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A R T I C L E
Synthesis of novel 6-enaminopurines
M. Alice Carvalho,a Magdi E. A. Zaki,a Yolanda Álvares,a M. Fernanda Proença*a and
Brian L. Boothb
a
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057, Braga,
Portugal. E-mail: fproenca@quimica.uminho.pt; Fax: +351 253 678983; Tel: +351 253 604379
Chemistry Department, University of Manchester Institute of Science and Technology,
b
Manchester, UK M60 1QD
Received 6th May 2004, Accepted 14th June 2004
First published as an Advance Article on the web 27th July 2004
Two different approaches have been used for the synthesis of 6-enaminopurines 6 from 5-amino-4-cyanoformimidoyl
imidazoles 1. In the first approach imidazoles 1 were reacted with ethoxymethylenemalononitrile or ethoxy-
methylenecyanoacetate under mild experimental conditions and this led to 9-substituted-6-(1-amino-2,2-dicyanovinyl)
purines 6a–f or 9-substituted-6-(1-amino-2-cyano-2-methoxycarbonylvinyl) purines 6g–k. These reactions are postulated
to occur through an imidazo-pyrrolidine intermediate 7, which rapidly rearranges to the 6-enaminopurine 6.
In the second approach 6-methoxyformimidoyl purines 3, prepared in two efficient steps from 5-amino-4-cyano-
formimidoyl imidazoles 1, were reacted with malononitrile and methylcyanoacetate with a mild acid catalysis (ammonium
acetate or piperidinium acetate) to give 6-enaminopurines 6a, 6d, 6f, 6g and 6k in very good yields. Only low yields were
obtained for the 6-enaminopurine 6j, as competing nucleophilic attack on C-8 of either 3d or 6j causes ring opening with
formation of pyrimido-pyrimidines 11 and 10a respectively.
from a singlet at  7.27 ppm integrating for one proton, indicative of
an imidazole ring; a proton at  6.57 ppm for a pyrrolidine substitu-
ent and a broad singlet at  6.07 ppm (2H) for an amino group in
the 5-position of an imidazole ring. The reaction was monitored by
measurement of the disappearance of the methyl signal of the OEt
group in 5a ( 1.42 ppm) with the appearance of a similar signal at 
1.24 ppm for the intermediate 7. The appearance of the final product
6c could not be measured directly as it precipitates from solution, but
the formation of the ethanol by-product (Me signal at  1.17 ppm)
could be measured. The results also indicate that the product is pres-
ent in 50% yield after approximately 40 min at 20 °C.
The 6-enaminopurine 6b could also be prepared from amidine 9
(Scheme 3), the precursor of imidazole 1b. These amidines promptly
cyclize in the presence of DBU,8 using ethanol as solvent, and eth-
oxymethylenemalononitrile was added directly to the reaction mix-
ture, avoiding the isolation step of 1b. The product 6b precipitates
from solution and was isolated in 91% yield.
When the N-aryl imidazoles 1a–d were combined with ethoxy-
methylenecyanoacetate (1.5 equiv.) a slower reaction occurred. The
pure product was again isolated upon filtration of the reaction mix-
ture, except when the aryl group is 4-cyanophenyl, where the low
solubility of imidazole 1d in the solvent system (acetonitrile:DMF,
5:3) results in a prolonged reaction time (5 days at room tempera-
ture). The product 6j remains in solution and the work up procedure
results in lower isolated yields of this compound.
Introduction
The biological importance of the purine structure is evident from the
countless derivatives that have been prepared and are active, especially
as antiviral1,2 and antitumour1,3 agents. The substituent in the 6-posi-
tion plays an important role in the potency and selectivity of the purine
derivatives. As a result, great efforts have been directed to the syn-
thesis and biological evaluation of a number of 6-substituted purines.
These compounds are usually prepared from the appropriate 6-halo-
genopurine by halogen-displacement reactions, including the use of
acid-catalyzed cross-coupling reactions. To our knowledge, however,
only a few methods were reported for the introduction of an enamine
moiety in the 6-position of the purine ring. The 6-(2′-aminomethylene)
group is usually generated by catalytic hydrogenation of the 6-cyano-
methylene substituent, which can be prepared in high yield by reaction
of the sodium salt of an activated cyanomethylene such as malononi-
trile,4 -cyanoacetamide5 and ethylcyanoacetate6 with 6-halogenated
or methylsulfonated purine derivatives.An earlier synthesis of a 6-(2′-
arylaminomethylene)purine uses 6-methylpurine as the starting mate-
rial. The reaction with the Vilsmeyer reagent in the presence of aniline
or substituted aniline, ultimately leads to the product.7
The present work describes the synthesis of 9-substituted-6-(1′-
aminomethylene)purines using two different but equally efficient
approaches. To our knowledge, the preparation of these compounds
has not been reported in the literature.
The reaction between N-alkyl imidazole 1e and ethoxymethyle-
nemalononitrile (1.2–1.5 equiv.) was only carried out in acetonitrile,
and as both the reagents and product are very soluble in this solvent
this caused difficulties in isolating the pure product from the reac-
tion mixture resulting in the low isolated yield of purine 6e (29%).
The structure of the 6-enaminopurines 6 was assigned on the basis
of elemental analysis and spectroscopic data. For purines 6a–f, the
two cyano groups are usually present in the IR spectrum as two
distinct and intense bands in the regions of 2215–2225 cm−1 and
2200–2210 cm−1. In the 13C NMR spectrum, the signals for both
cyano groups are also clearly identified around  115 and  116 ppm.
Another typical feature is the chemical shift of both carbon atoms of
the alkene substituent in the 6-position of the purine ring. The carbon
atom directly bonded to the amino group gives a signal around 
165 ppm, while the adjacent carbon (bonded to the two cyano
groups) leads to a small band (absent in the spectrum of 6e) around 
50 ppm. In the 1H NMR spectrum, the amino group leads to two sin-
glets around  9.10 ppm and  9.40 ppm, each one integrating for one
Results and discussion
The reaction of N-aryl-5-amino-4-cyanoformimidoyl imidazoles
1a–d with ethoxymethylenemalononitrile (1.5 equiv.) at room tem-
perature, using acetonitrile or a combination of acetonitrile and DMF
assolvent(Scheme1)gavethe6-enaminopurines 6.Theseprecipitate
from the reaction mixture and can be isolated in high yields, as a pure
product, after filtration. The reaction is usually fast (6 h at room tem-
perature) except when the 1-(4-cyanophenyl)imidazole 1d is used as
the starting material. In this case, the poor solubility of the imidazole
in acetonitrile:DMF (5:2) leads to a much slower reaction (3 days at
room temperature).Amechanism for this reaction (Scheme 2) is pro-
posed on the basis of a 1H NMR study on the evolution of imidazole
1c (R = 4-FC6H4) in the presence of ethoxymethylenemalononitrile
(3 equiv.) in a deuterated acetonitrile solution (Fig. 1). Only one inter-
mediate species could be detected during a clean reaction leading
to product 6c. The concentration of this compound does not exceed
6% but its signals are clearly identifiable as structure 7 (Scheme 2)
2 3 4 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 4 0 – 2 3 4 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Scheme 1
Scheme 3
proton, or to a broad singlet between  9.20–9.30 ppm integrating for
two protons (6c). The two signals in the  9.0–9.4 ppm region for the
two C–H protons on C-2 and C-8 support the presence of the purine
ring. For purines 6i–k, the IR spectrum shows the cyano group as
an intense band around 2210 cm−1 and the stretching vibration of
the carbonyl group is also an intense band in the 1675–1715 cm−1
region. The presence of these two functional groups is confirmed
in the 13C NMR spectrum, as two peaks are always present around
 118 ppm (CN) and  164 ppm (CO). The chemical shifts for both
carbon atoms of the alkene substituent in the 6-position of the pu-
rine ring are also typical of these compounds and reflect the effect
of the substituent. The carbon atom directly bonded to the amino
group gives a signal around  167 ppm, while the adjacent carbon
(bonded to the cyano and ester groups) leads to a small band around
 71 ppm. In the 1H NMR spectrum, the amino group leads to two
singlets around  9.20 ppm and  9.40 ppm, each one integrating for
one proton, and the two signals in the  9.1–9.4 ppm region for the
two C–H protons on C-2 and C-8 are indicative of the purine ring.
Further support for the structure of purines 6 was obtained when
the same compounds were prepared by the reaction of 6-(methoxy-
formimidoyl)purines 3 and malononitrile or methylcyanoacetate
(Scheme 1). The synthesis of 6-(methoxyformimidoyl)purines 3 has
been recently reported and occurs in excellent yield from the reac-
tion of 6-cyanopurines 2 with methanol in the presence of DBU.9
The 6-cyanopurines used in this work were prepared in a simple and
efficient way from the reaction of imidazoles 1 with triethylortho-
formate in the presence of sulfuric acid or with dimethylformamide
diethylacetal.10
Scheme 2
Fig. 1 The diagram represents the consumption of 5a () (Me signal of
the OEt group at  1.42 ppm), the formation of the intermediate 7c () (Me
signal of the OEt group at  1.24 ppm) and its evolution to the purine 6c
() (Me signal of the OEt group of EtOH at  1.17 ppm).
The chemistry of the imidate function has been thoroughly re-
viewed11 and indicates that this functional group is susceptible to
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 4 0 – 2 3 4 5
2 3 4 1

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nucleophilic substitution, that usually occurs with elimination of
the ether function. In the present work, a detailed study was car-
ried out on the reaction of purines 3a, 3d and 3f with malononitrile
and methylcyanoacetate, in order to generate the corresponding
6-enaminopurines 6. This reaction is very slow or does not occur
in the absence of mild acid catalysis, even when an excess of the
carbon acid is used (1.1–1.4 equivalents) and under reflux condi-
tions in acetonitrile or dichloromethane. When ammonium acetate
or piperidinium acetate were used as catalysts and the reaction
was carried out under reflux in acetonitrile or dichloromethane,
the 6-enaminopurine was formed and precipitated from the reac-
tion mixture on cooling. The reaction of 9-(4-cyanophenyl)-6-
(methoxyformimidoyl)purine 3d with methylcyanoacetate is slow
even in the presence of pyridinium acetate. In order to overcome
this problem, four equivalents of methylcyanoacetate were used and
the reflux in acetonitrile was maintained for up to 8 days. The ex-
perimental conditions favored ring opening of the 6-enaminopurine
ring, leading to the formation of pyrimido-pyrimidine 10a in vari-
able quantities (Scheme 4). A small amount of purine 6j (17%)
could be isolated when 6-(methoxyformimidoyl)purine 3d and
methylcyanoacetate (4 equivalents) were refluxed in acetonitrile
for 3.5 days, in the presence of a catalytic amount of piperidinium
acetate. In this reaction, compound 10a was isolated as the major
product (53%). When the acid catalysis was replaced by base ca-
talysis (DBU), the only product isolated after 2 days under reflux in
dry acetonitrile was the pyrimido-pyrimidine 10a (40%). The use of
an excess of base (DMAP, 6 equivalents) also caused ring opening
of the 6-(methoxyformimidoyl)purine, and the solid isolated was a
mixture of pyrimido-pyrimidines 10a and 11 in a 1:3 molar ratio,
as indicated by 1H NMR spectroscopy (Scheme 5). Ring opening of
the 6-enaminopurine was confirmed when compound 6g was reacted
with methylcyanoacetate (8 equivalents) in the presence of DMAP
(1.3 equivalents). The only product isolated from the reaction mix-
ture was the pyrimido-pyrimidine 10b (70%). The observation that
direct ring opening of purine 3d is favored by the addition of an ex-
cess of base, indicates that when a high concentration of the methyl
cyanoacetate anion is present, competitive nucleophilic attack on C-8
of the purine ring occurs to give the pyrimido-pyrimidine 11 through
an ANRORC type mechanism, as is represented in Scheme 5. This
pathway must be facilitated by the electron-withdrawing effect of the
aryl substituent on N-9. Under mild acid catalysis the concentration
of the carbon acid in solution is high and protonation of the imidate
function also occurs, activating it for nucleophilic attack, resulting in
6-enaminopurine formation (Scheme 5).
Scheme 4
Conclusion
The reaction of 5-amino-4-(cyanoformimidoyl)imidazoles
1
with ethoxymethylenemalononitrile 5a or ethoxymethylene-
cyanoacetate 5b occurs selectively on the cyanoformimidoyl
substituent. An imidazo-pyrrolidine structure was postulated for
the intermediate, which rapidly evolves to the 6-enaminopurine 6,
isolated in very good yield. The electronic effect of the substituent
on N-1 of the imidazole ring does not seem to affect the efficiency
of this reaction.
The same 6-enaminopurines were isolated from the reaction of
6-(methoxyformimidoyl) purines 3 with malononitrile 4a or methyl-
cyanoacetate 4b, in the presence of mild acid catalysis. Although
this reaction sequence requires three steps, starting from imidazole
1, the overall yield is only slightly lower when compared to the other
synthetic method, as the 6-cyanopurines 2 and the 6-(methoxyform
imidoyl)purines 3 can be prepared in almost quantitative yields.9
Major problems were faced when purine 3d (R = 4-NCC6H4) was
reacted with methylcyanoacetate 4b. The reaction does not occur or
is rather slow in the presence of acid catalysis and the addition of
base causes ring opening of the imidazole ring in purine 3d and/or
6j leading to pyrimido-pyrimidines 11 and 10 respectively.
Experimental section
IR Spectra were recorded on a Perkin-Elmer 1600 series FTIR spec-
trometer, 1H and 13C NMR spectra on a Varian Unity Plus spectro-
Scheme 5
2 3 4 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 4 0 – 2 3 4 5

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meter. Mass spectra were recorded on a GC-MS Automass 120 or
on a Kratos Concept instrument.
and NH), 9.15 (1 H, s, 2-H), 7.81 (2 H, d, J 6.9 Hz, Ar–H), 7.20
(2 H, d, J 6.9 Hz,Ar–H), 3.84 (3H, s, OMe); C (75 MHz; (CD3)2SO)
165.4, 159.2, 152.2, 148.9, 148.0, 131.0, 126.6, 125.4, 115.7, 114.9,
114.8, 55.6, 50.4.
The 6-cyanopurines 2a, 2d and 2f were prepared according to
the experimental procedure described in the literature.10 These
compounds were used as precursors of the corresponding 6-
(methoxyformimidoyl)purines 3a, 3d and 3f using previously
described experimental procedures.9
9-(4-Toluyl)-6-(1-amino-2,2-dicyanovinyl)purine (6b)
Mp 298–299 °C; (Found: C, 63.03; H, 3.95; N, 31.97. Calc. for
C16H11N7.0.20H2O: C, 63.03; H, 3.74; N, 32.17%); IR (Nujol mull):
General procedure for the reaction of 5-amino-1-aryl-4-(cyano-
formimidoyl)imidazoles 1 with ethoxymethylenemalononitrile

max/cm−1 2207s (CN), 1662s, 1545s; H (300 MHz; (CD3)2SO) 9.41
(1 H, s, NH), 9.21 (1 H, s, 2-H), 9.16 (1 H, s, 8-H), 7.80 (2 H, d,
J 8.3 Hz, Ar–H), 7.45 (2 H, d, J 8.3 Hz, Ar–H), 2.41 (3 H, s, Me);
C NMR (75 MHz; (CD3)2SO) 165.4, 152.3, 152.1, 148.0, 147.7,
138.3, 131.4, 131.2, 130.2, 123.6, 115.7, 114.9, 50.5, 20.7.
A suspension of 5-amino-1-aryl-4-(cyanoformimidoyl)imidazole
1a–d (0.41–0.44 mmol) in acetonitrile (5 mL) and DMF (1 mL) for
1a, acetonitrile (5 mL) for 1b and 1c or acetonitrile (5 mL) and DMF
(2 mL) for 1d, was combined with ethoxymethylenemalononitrile
(0.66 mmol) at 0 °C. The mixture was stirred in the ice bath for 1 h
and then at room temperature for 6 h (for 1a–c) or 72 h (for 1d). The
suspension was filtered and washed with diethyl ether. The product
was identified as 6-(1-amino-2,2-dicyanovinyl)-9-arylpurine 6a–d.
9-(4-Fluorophenyl)-6-(1-amino-2,2-dicyanovinyl)purine (6c)
Mp 314–315 °C; (Found: C, 59.05; H, 2.88. Calc. for C15H8N7F:
C, 59.02; H, 2.62%); IR (Nujol mull): max/cm−1 2217s (CN), 2200s
(CN), 1665s, 1580m, 1550s, 1517s; H (300 MHz; (CD3)2SO) 9.27
(2 H, br s, NH2), 9.19 (1 H, s, 2-H), 9.16 (1 H, s, 8-H), 7.96 (2 H, dd,
J 9.0 Hz, J 4.5 Hz, Ar–H), 7.51 (2 H, t, J 9.0 Hz, Ar–H); C NMR
(75 MHz; (CD3)2SO) 165.4, 163.2 (d, J 244 Hz), 152.4, 152.3,
148.1, 147.8, 131.2, 130.2 (d, J 3 Hz), 126.3 (d, J 9 Hz), 116.8 (J
23 Hz), 115.8, 115.0, 50.6.
General procedure for the reaction of 1-alkyl-5-amino-4-
(cyanoformimidoyl)imidazoles 1 with ethoxymethylene-
malononitrile
A solution of 1-alkyl-5-amino-4-(cyanoformimidoyl)imidazole
1e, f (0.45–0.54 mmol) in acetonitrile (5 mL) was combined with
ethoxymethylenemalononitrile (0.66 mmol) at 0 °C (for 1f) or room
temperature (for 1e). The solution was stirred in the ice bath for 1 h
and then at room temperature for 1 h (for 1f) or 18 h (for 1e). Com-
pound 6f precipitates from the reaction mixture and was filtered
and washed with diethyl ether. Compound 6e remains in solution,
which is concentrated in the rotary evaporator. This product was
precipitated by addition of dichloromethane and was filtered and
washed with dichloromethane. The product was identified as 6-(1-
amino-2,2-dicyanovinyl)-9-alkylpurine 6e, f.
9-(4-Cyanophenyl)-6-(1-amino-2,2-dicyanovinyl)purine (6d)
Mp 270 °C (dec.); IR (Nujol mull): max/cm−1 2234w (CN), 2219m
(CN), 2205m (CN), 1661m, 1534s, 1519s; H (300 MHz; (CD3)2SO)
9.42 (1 H, s, NH), 9.38 (1 H, s, 2-H), 9.22 (1 H, s, 8-H), 9.18 (1 H,
s, NH), 8.28 (2 H, d, J 8.4 Hz, Ar–H), 8.17 (2 H, d, J 8.4 Hz, Ar–H);
C (75 MHz; (CD3)2SO) 165.2, 152.6, 152.0, 148.4, 147.3, 137.7,
134.0, 131.6, 123.8, 118.2, 115.7, 114.8, 110.8, 50.6. HRMS (FAB)
m/z (FAB) 313.096447 ((M + H)+. C16H8N8 requires 313.095017).
General procedure for the reaction of 5-amino-1-aryl-4-(cyano-
formimidoyl)imidazoles 1 with ethoxymethylenecyanoacetate
9-Benzyl-6-(1-amino-2,2-dicyanovinyl)purine (6e)
Mp 187–189 °C (dec.); H (300 MHz; (CD3)2SO) 9.35 (1 H, s, NH),
9.11 (1 H, s, 2-H), 9.10 (1 H, s, NH), 8.99 (1 H, s, 8-H), 7.35 (5 H,
m, Ph), 5.57 (2 H, s, CH2Ph); C (75 MHz; (CD3)2SO) 165.5, 152.4,
151.8, 148.8, 147.6, 136.1, 130.7, 128.8, 128.2, 127.9, 115.7, 114.9,
46.9.
A suspension of 5-amino-1-aryl-4-(cyanoformimidoyl)imidazole
1a–d (0.40–0.44 mmol) in acetonitrile (5 mL) and DMF (1 mL) for
1a, acetonitrile (5 mL) for 1b and 1c or acetonitrile (5 mL) and DMF
(3 mL) for 1d, was combined with ethoxymethylenecyanoacetate
(0.60–0.90 mmol) at 0 °C (for 1a, 1b) or room temperature (for 1c,
1d). The mixture was stirred in the ice bath for 4 h and than for 2 days
at −10 °C (for 1a and 1b), for 10 h at room temperature (for 1c) or
for 5 days at room temperature (for 1d). Compounds 6g, 6h and 6i
precipitate out of solution and were filtered and washed with ethanol.
Compound 6j remains in solution, which is concentrated in the rotary
evaporator. The product was precipitated by addition of diethyl ether
and was filtered and washed with ether. The solid was identified as
6-(1-amino-2-cyano-2-methoxycarbonylvinyl)-9-aryl purine 6g–j.
9-Methyl-6-(1-amino-2,2-dicyanovinyl)purine (6f)
Mp 268 °C (dec.); IR (Nujol mull): max/cm−1 2220m (CN), 2202m
(CN), 1662m, 1586m, 1553s, 1504m; H (300 MHz; (CD3)2SO)
9.22 (2 H, br s, NH2), 9.10 (1 H, s, 2-H), 8.77 (1 H, s, 8-H), 3.90
(3 H, s, Me); C (75 MHz; (CD3)2SO) 165.6, 152.9, 151.5, 149.5,
147.1, 130.5, 115.8, 115.0, 50.3, 30.0. HRMS (FAB) m/z (FAB)
226.0843444 ((M + H)+. C10H7N7 requires 226.084118).
9-(4-Methoxyphenyl)-6-(1-amino-2-cyano-2-methoxy-
carbonylvinyl)purine (6g)
Synthesis of 9-(4-toluyl)-6-(1-amino-2,2-dicyanovinyl)purine
6b from N-(4-toluyl)-N′-(2-amino-1,2-dicyanovinyl)-
formamidine 9 and ethoxymethylenecyanoacetate
Mp 222–224 °C; (Found: C, 58.04; H, 4.22; N, 23.64. Calc. for
C17H14N6O3: C, 52.28; H, 4.03; N, 23.99%); IR (Nujol mull):
A
suspension of N-(4-toluyl)-N′-(2-amino-1,2-dicyanovinyl)-

max/cm−1 2195m (CN), 1677m (CO), 1611m, 1576m, 1520s; H
formamidine (0.10 g, 0.44 mmol) in ethanol (5 mL) was combined
with one drop of DBU and the mixture was stirred at room tempera-
ture for 10 min and then placed in an ice bath. Ethoxymethylene-
cyanoacetate (0.09 g, 0.74 mmol) was added and the mixture was
stirred at 0 °C for 1 h followed by 6 h at room temperature. The
product precipitates out of solution and was filtered and washed
with diethyl ether. The solid was identified as the title compound
(0.12 g, 0.40 mmol, 91%).
(300 MHz; (CD3)2SO) 9.36 (1 H, s, NH), 9.19 (1 H, s, NH), 9.13
(1 H, s, 8-H), 9.12 (1 H, s, 2-H), 7.81 (2 H, d, J 9.0 Hz, Ar–H),
7.19 (2 H, d, J 9.0 Hz, Ar–H), 3.85, (3 H, s, OMe), 3.76 (3 H, s,
COOMe); C (75 MHz; (CD3)2SO) 167.0, 163.9, 159.1, 152.3,
151.9, 150.1, 147.4, 131.1, 126.7, 125.3, 114.9, 71.2, 55.6, 51.6.
9-(4-Toluyl)-6-(1-amino-2-cyano-2-methoxycarbonyl-
vinyl)purine (6h)
9-(4-Methoxyphenyl)-6-(1-amino-2,2-dicyanovinyl)purine (6a)
Mp 242–243 °C; (Found: C, 61.28; H, 4.42; N, 25.03. Calc.
for C17H14N6O2: C, 61.07; H, 4.22; N, 25.14%); H (300 MHz;
(CD3)2SO) 9.37 (1 H, s, NH), 9.20 (1 H, s, NH), 9.17 (1 H, s,
8-H), 9.15 (1 H, s, 2-H), 7.82 (2 H, d, J 8.4 Hz, Ar–H), 7.46 (2 H,
d, J 8.4 Hz, Ar–H), 3.76, (3 H, s, COOMe), 2.41 (3 H, s, Me); C
Mp 309–310 °C; (Found: C, 59.97; H, 3.75; N, 30.16. Calc. for
C16H11N7O.0.25H2O: C, 59.72; H, 3.58; N, 30.48%); IR (Nujol
mull): max/cm−1 2216s (CN), 2206m (CN), 1665s, 1579m, 1544s;
H (300 MHz; (CD3)2SO) 9.40 (1 H, br s, NH), 9.17 (>1 H, s, 8-H
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 4 0 – 2 3 4 5
2 3 4 3

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of the starting material. The cream solid was filtered and washed
with diethyl ether. The mother liquor was concentrated in the ro-
tary evaporator leading to a second crop of the same product. The
compound was identified as the 6-(1-amino-2,2-dicyanovinyl)-9-
(4-methoxyphenyl) purine 6g (0.13 g, 0.38 mmol, 69%).
(75 MHz; (CD3)2SO) 166.9, 163.8, 152.3, 151.8, 150.2, 147.2,
138.1, 131.4, 131.2, 130.1, 123.4, 117.6, 71.2, 51.5, 20.7.
9-(4-Fluorophenyl)-6-(1-amino-2-cyano-2-methoxycarbonyl-
vinyl)purine (6i)
Mp 250–254 °C (dec); (Found: C, 56.73; H, 3.62. Calc. for
C16H11N6O2F: C, 56.81; H, 3.28%); IR (Nujol mull): max/cm−1 2208s
(CN), 1676m (CO), 1626s, 1582m, 1573s, 1524s; H (300 MHz;
(CD3)2SO) 9.38 (1 H, s, NH), 9.22 (1 H, s, NH), 9.19 (1 H, s, 8-H),
9.16 (1 H, s, 2-H), 8.00 (2 H, dd, J 9.0 Hz, J 4.8 Hz,Ar–H), 7.52 (2 H,
t, J 9.0 Hz, Ar–H), 3.76 (3 H, s, COOMe); C (75 MHz; (CD3)2SO)
167.0, 163.8, 161.6 (d, J 245 Hz), 152.5, 151.9, 150.2, 147.3, 131.2,
130.3, 126.1 (d, J 9 Hz), 117.7, 116.7 (d, J 23 Hz), 71.2, 51.6.
Reaction of 9-(4-cyanophenyl)-6-(methoxyformimidoyl)purine
3d with methylcyanoacetate
Method A. A suspension of 9-(4-cyanophenyl)-6-(methoxy-
formimidoyl)purine 3d (0.15 g, 0.55 mmol) in acetonitrile (20 mL),
was combined with methylcyanoacetate (0.22 g, 2.20 mmol) and a
catalytic amount of piperidinium acetate, at room temperature. The
suspension was refluxed for 3.5 days, when the yellow suspension
was filtered while still hot, and washed with acetonitrile and di-
ethyl ether. This product was identified as the pyrimido-pyrimidine
10a (0.10 g, 0.29 mmol, 53%); mp 241 °C (dec); IR (Nujol mull):
9-(4-Cyanophenyl)-6-(1-amino-2-cyano-2-methoxycarbonyl-
vinyl)purine (6j)

max/cm−1 2225m (CN), 2209m (CN), 1677m (CO), 1596s, 1584s,
Mp 204 °C (dec.); (Found: C, 59.28; H, 3.29; N, 28.34. Calc.
for C17H11N7O2: C, 59.13; H, 3.19; N, 28.41%); IR (Nujol mull):
1529s; H (300 MHz; (CD3)2SO) 13.60 (1 H, s, NH), 10.46 (1 H, s,
NH), 8.75 (1 H, s, 2-H), 8.49 (1 H, d, J 3.6 Hz, 7-H), 8.24 (2 H, d, J
8.7 Hz,Ar–H), 7.83 (2 H, d, J 8.7 Hz,Ar–H), 3.81 (3 H, s, COOMe).
HRMS (FAB) m/z (FAB) 346.1052 ((M + H)+. C17H12N7O2 requires
346.1052). The mother liquor was concentrated to a viscous oil and
addition of ethanol and diethyl ether led to a yellow solid, which
was filtered and washed with diethyl ether. This product was identi-
fied as the 6-(1-amino-2,2-dicyanovinyl)-9-(4-cyanophenyl) purine
6j (0.03 g, 0.09 mmol, 17%).

max/cm−1 2230m (CN), 2208m (CN), 1664m (CO), 1615m, 1579m;
H (300 MHz; (CD3)2SO) 9.37 (1 H, s, 8-H), 9.35 (1 H, s, NH), 9.22
(2 H, s, 2-H and NH), 8.30 (2 H, d, J 8.7 Hz, Ar–H), 8.17 (2 H, d,
J 8.7 Hz, Ar–H), 3.76 (3 H, s, COOMe); C (75 MHz; (CD3)2SO)
166.9, 163.6, 152.6, 151.6, 150.5, 146.9, 137.8, 134.1, 131.6, 123.6,
118.2, 117.6, 110.6, 71.5, 51.6.
9-Methyl-6-(1-amino-2-cyano-2-methoxycarbonylvinyl)purine
(6k)
Method B.Asolution of methylcyanoacetate (0.05 g, 0.46 mmol)
in dry acetonitrile (5 mL) was combined with a catalytic amount
of DBU, at room temperature. 9-(4-Cyanophenyl)-6-(methoxy-
formimidoyl)purine 3d (0.12 g, 0.42 mmol) was added and the
suspension was efficiently stirred at room temperature for 15 h.
The mixture was refluxed for 2 days and then allowed to stand at
room temperature for another 2.5 days.Ayellow-greenish solid was
filtered, washed with diethyl ether and identified as the pyrimido-
pyrimidine 10a (0.06 g, 0.17 mmol, 40%).
Mp 206–207 °C; (Found: C, 50.97; H, 3.91; N, 32.32. Calc. for
C11H10N6O: C, 51.16; H, 3.88; N, 32.56%); IR (Nujol mull):

1530s; H (300 MHz; (CD3)2SO) 9.33 (1 H, s, NH), 9.17 (1 H, br s,
NH), 9.08 (1 H, s, 2-H), 8.72 (1 H, s, 8-H), 3.90 (3 H, s, Me), 3.73
(3 H, s, COOMe); C (75 MHz; (CD3)2SO) 167.0, 164.2, 152.7,
151.6, 149.3, 149.0, 130.5, 117.7, 71.1, 51.5, 29.9.
max/cm−1 2208m (CN), 1683m (CO), 1630m, 1593m, 1580m,
General procedure for the reaction of 9-aryl-6-(methoxy-
formimidoyl)purine 3 with malononitrile
Method C.Asolution of methylcyanoacetate (0.42 g, 4.20 mmol)
and dimethylaminopyridine (0.60 g, 4.89 mmol) in DMF (4 mL)
was combined with 9-(4-cyanophenyl)-6-(methoxyformimidoyl)-
purine 3d (0.23 g, 0.83 mmol) at room temperature. The white
suspension was efficiently stirred at room temperature and after 2.5
days the pale yellow solid was filtered and washed with ethanol and
diethyl ether, leading to 0.15 g of a mixture of pyrimido-pyrimidines
10a and 11 in a 1:3 ratio (by 1H NMR). A second crop of solid was
isolated after slow evaporation of the solvent. This product was
identified as the pyrimido-pyrimidine 11 (0.03 g, 0.11 mmol, 13%);
mp 209 °C (dec); IR (Nujol mull): max/cm−1 2220m (CN), 1605s,
1585m, 1557m, 1532s; H (300 MHz; (CD3)2SO) 10.67 (1 H, s, NH),
8.93 (1 H, s, 7-H), 8.79 (1 H, s, 2-H), 8.31 (2 H, d, J 8.7 Hz, Ar–H),
7.84 (2 H, d, J 8.7 Hz, Ar–H), 4.14 (3 H, s, OMe); C (75 MHz;
(CD3)2SO) 165.9, 156.7, 155.8, 153.8, 142.9, 134.7, 133.9, 132.9,
121.5, 119.2, 105.3, 55.0. HRMS (FAB) m/z (FAB) 279.098929
((M + H)+. C14H10N6O requires 279.099434).
A
suspension of 9-aryl-6-(methoxyformimidoyl)purine
3
(0.55 mmol) in dichloromethane (5 mL) for 3a or dichloromethane
(4 mL) and ethanol (2 mL) for 3d, was combined with malononi-
trile (0.84 mmol) and a catalytic amount of ammonium acetate, at
room temperature. The mixture was stirred for 1 day (for 3a) or 6
days (for 3d). The suspension was filtered and washed with diethyl
ether. Asecond crop of the same product could be obtained from the
mother liquor after concentration in the rotary evaporator and addi-
tion of diethyl ether. The product was identified as the correspond-
ing 6-(1-amino-2,2-dicyanovinyl)-9-arylpurines 6a and 6d.
Reaction of 9-methyl-6-(methoxyformimidoyl)purine 3f with
malononitrile
A solution of 9-methyl-6-(methoxyformimidoyl)purine 3f (0.15 g,
0.80 mmol) in dichloromethane (5 mL), was combined with malono-
nitrile (0.07 g, 1.12 mmol) and a catalytic amount of ammonium
acetate, at room temperature and with efficient stirring. A cream
solid started to be formed after 10 min, and the mixture was stirred
for 4.5 days, when the tlc showed the absence of the starting ma-
terial. The suspension was filtered and washed with diethyl ether.
The product was identified as the 6-(1-amino-2,2-dicyanovinyl)-9-
methyl purine 6f.
Reaction of 9-(4-methoxyphenyl)-6-(1-amino-2-cyano-2-
methoxycarbonylvinyl)purine 6g with methylcyanoacetate
A solution of purine 6g (0.02 g, 0.06 mmol) in DMF (2 mL) was
combined with DMAP (0.01 g, 0.08 mmol) and the mixture was
stirred at room temperature. Addition of methylcyanoacetate
(0.05 g, 0.51 mmol) and stirring at room temperature for 5 h
led to the formation of a solid suspension. After another 14 h at
room temperature, the yellow solid was filtered and washed with
ethanol. This product was identified as the pyrimido-pyrimidine
10b (0.014 g, 0.04 mmol, 70%); mp 264–266 °C (dec); (Found: C,
58.16; H, 4.17; N, 23.75. Calc. for C17H14N6O3: C, 58.29; H, 4.00;
N, 24.00%); IR (Nujol mull): max/cm−1 3348m (NH), 2207m (CN),
1666w (CO), 1604s, 1576s, 1584s, 1552s; H (300 MHz; (CD3)2SO)
13.52 (1 H, s, NH), 9.95 (1 H, s, NH), 8.53 (1 H, s, 2-H), 8.45 (1 H,
Reaction of 9-(4-methoxphenyl)-6-(methoxyformimidoyl)-
purine 3a with methylcyanoacetate
A suspension of 9-(4-methoxyphenyl)-6-(methoxyformimidoyl)-
purine 3a (0.15 g, 0.55 mmol) in dichloromethane (5 mL), was
combined with methylcyanoacetate (0.22 g, 2.20 mmol) and a
catalytic amount of ammonium acetate, at room temperature. The
suspension was refluxed for 21 h, when the tlc showed the absence
2 3 4 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 4 0 – 2 3 4 5

View Article Online
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s, 7-H), 7.78 (2 H, d, J 9.0 Hz, Ar–H), 6.96 (2 H, d, J 9.0 Hz, Ar–H),
3.77 (3 H, s, COOMe), 3.75 (3 H, s, OMe).
Reaction of 9-methyl-6-(methoxyformimidoyl)purine 3f with
methylcyanoacetate
A solution of methylcyanoacetate (0.12 g, 1.17 mmol) in dichloro-
methane (5 mL) was combined with a catalytic amount of
piperidinium acetate and the mixture was efficiently stirred at room
temperaturefor35min.Additionof9-methyl-6-methoxyformimidoyl
purine 3f (0.15 g, 0.78 mmol) led to a pale yellow solution, which
was refluxed for 2 days. The solution was concentrated in the rotary
evaporator and addition of acetonitrile, THF and diethyl ether led to
a solid product, which was filtered and washed with THF and diethyl
ether. The product was identified as the 6-(1-amino-2,2-dicyano-
vinyl)-9-(4-methoxyphenyl) purine 6k (0.15 g, 0.61 mmol, 77%).
Acknowledgements
The authors gratefully acknowledge the financial support by the
University of Minho and Fundação para a Ciência e Tecnologia
(project PRAXIS/C/QUI/10101/1998).
10 (a) B. L. Booth,
R. D. Coster
and
M. F. Proença,
Synthe-
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R. G. Pritchard and M. F. Proença, J. Heterocyclic Chem., 1997,
739; (c) A. Al-Azmi, B. L. Booth, R. A. Carpenter, M. A. Carvalho,
E. Marrelec, R. G. Pritchard and M. F. Proença, J. Chem. Soc., Perkin
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 4 0 – 2 3 4 5
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