Efficient conversion of 6-cyanopurines into 6-alkoxyformimidoyl-purines

Article abstract of DOI:10.1039/b400171k

An extremely simple method for the selective synthesis of 9-aryl and 9-alkyl 6-alkoxy or 6-alkoxyformimidoylpurines from the corresponding 6-cyanopurines is described. The reaction is carried out with methanol or ethanol in the presence of DBU. At room temperature, nucleophilic attack by the primary alcohol occurs selectively on the cyano carbon atom, leading to 6-alkoxyformimidoylpurines in good yields. Heating the reaction mixture at a temperature greater than or equal to 78°C leads to nucleophilic substitution of the substituent in the 6-position by the alkoxy group, generating the corresponding 6-alkoxypurines, also in excellent yields. The 6-alkoxyformimidoylpurines were used as intermediates in the synthesis of 6-carboxamidinopurines by reaction with methylamine (for 9-methylpurine 5a) or methyl ammonium chloride (for 9-arylpurines 5b and 5c).

Full text of DOI:10.1039/b400171k

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Efficient conversion of 6-cyanopurines into 6-alkoxyformimidoyl-
purines
M. Alice Carvalho,a Teresa M. Esteves,a M. Fernanda Proença*a and Brian L. Boothb
a Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710 Braga, Portugal.
E-mail: fproenca@quimica.uminho.pt; Fax: ϩ351 253 678983; Tel: ϩ351 253 604379
b Chemistry Department, University of Manchester Institute of Science and Technology,
Manchester, UK M60 1QD
Received 8th January 2004, Accepted 13th February 2004
First published as an Advance Article on the web 4th March 2004
An extremely simple method for the selective synthesis of 9-aryl and 9-alkyl 6-alkoxy or 6-alkoxyformimidoylpurines
from the corresponding 6-cyanopurines is described. The reaction is carried out with methanol or ethanol in the
presence of DBU. At room temperature, nucleophilic attack by the primary alcohol occurs selectively on the cyano
carbon atom, leading to 6-alkoxyformimidoylpurines in good yields. Heating the reaction mixture at a temperature
greater than or equal to 78 ЊC leads to nucleophilic substitution of the substituent in the 6-position by the alkoxy
group, generating the corresponding 6-alkoxypurines, also in excellent yields. The 6-alkoxyformimidoylpurines were
used as intermediates in the synthesis of 6-carboxamidinopurines by reaction with methylamine (for 9-methylpurine
5a) or methyl ammonium chloride (for 9-arylpurines 5b and 5c).
catalytic amount of sodium methoxide in methanol, followed
Introduction
by addition of ammonium chloride.6 Unlike these compounds,
6-alkoxypurines have been known for a few decades and two
major reviews have been produced about their chemistry.7,8
Their synthesis could be envisaged through direct alkylation of
the widely available oxopurines, but N- rather than O-alkylation
is favored. The recent application of O-alkylated phosphonates
and other reagents to O-alkylate oxopurines directly, has
improved the selectivity of this synthetic method.8 Neverthe-
less, almost all of the known 6-alkoxypurine derivatives have
been prepared by the standard nucleophilic displacement of a
halogen atom, usually chlorine. This method is only success-
ful when alkoxides are used and the reaction temperature is
kept below 100 ЊC. With higher temperatures, isomerization to
N-alkyl-oxopurines occurs.7,8 Other suitable groups have been
used for nucleophilic displacement, especially the methyl-
sulfonyl,9 alkylthio10,11,12 alkylseleno13,14 or 1,2,4-triazol-4-yl15
groups. The 6-trialkylammonium16,17 and 6-pyridinium18,19
salts have also been used effectively in this reaction.
In the last few decades, modified purine structures have been an
important source of a wide variety of biologically active
materials. The selective modification of substituents in the ring
is an important approach to prepare new purine derivatives. As
a consequence, the development of highly efficient methods for
these synthetic transformations is potentially very useful.
Recent work on the synthesis of 6-cyanopurines 21 has shown
that these compounds can be prepared in a simple and efficient
way from 5-amino-4-(cyanoformimidoyl)imidazoles 1 and tri-
ethyl orthoformate under reflux conditions or at room temper-
ature, in the presence of sulfuric acid (Scheme 1). Only a few
reactions are described in the literature for these com-
pounds,2,3,4 and to our knowledge, the nucleophilic substitution
of a cyano group in the 6-position of the purine ring by an
alkoxy group has never been reported.
An early publication on the reactivity of 6-cyanopurines
indicates that ethanol, in the presence of dry hydrogen chloride,
at low temperature, converts the cyano group into an imidate
function.5 The product was isolated as the hydrochloride and its
instability prevented purification and further characterization.
No further successful methods have been reported for the
synthesis of 6-alkoxyformimidoylpurines, although these
compounds were postulated as intermediates in the synthesis of
6-amidinopurines, when 6-cyanopurines were reacted with a
In the present work, we report a simple, mild and effective
method to generate 6-alkoxypurines or 6-alkoxyformimidoyl-
purines from 6-cyanopurines and methanol or ethanol in the
presence of DBU. The isolation of 6-alkoxyformimidoylpurines
obviates an important problem in the synthesis of 6-carbox-
amidinopurines 3 as these compounds can not be prepared
from 6-cyanopurines by direct reaction with ammonia or amine
Scheme 1 Reagents and conditions: a) HC(OEt)3; b) NH2Me (aq), CH2Cl2, rt.
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
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 1 9 – 1 0 2 4
1019

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Table 1
an attempt to accelerate the reaction, one equivalent of DBU
was added to a suspension of purine 2c in ethanol, and was
stirred at room temperature for 13 days. The solid mixture was
filtered and the H NMR spectrum on the solid indicated the
absence of starting material. The product was a mixture of
compounds 6c and 8c in approximately 1 : 1 ratio.
Compound
R
Reaction conditions
Yield (%)
1
5a
5b
Me
4-MeOC6H4
16 h (rt)
4 days (rt)
94
96
88
10 h (reflux)
10 days (rt)
13 days (rt)
3 days (78 ЊC)
25 h (78 ЊC)
17 h (78 ЊC)
4 h (reflux)
25 h (reflux)
3.5 days (rt)
40 min (reflux)
When the same reaction (2c and ethanol/DBU) was carried
out under reflux conditions, compound 8c was isolated in 82%
yield after only 40 minutes, and no trace of the 6-(ethoxy-
formimidoyl)purine 6c was detected by TLC on the reaction
mixture. In this case, nucleophilic aromatic substitution occurs
selectively, leading to the replacement of the substituent in
the 6-position by the ethoxy group. A similar reactivity was
registered when the 6-cyanopurines 2a and 2b were refluxed in
ethanol/DBU, leading to the corresponding 6-ethoxypurines 8a
(48%) and 8b (46%). Both 6-ethoxypurines 8a and 8b are very
soluble in the solvent mixture, leading to comparatively low
isolated yields of these products. However, the TLC indicates
that a complete and clean reaction occurs in each case. The
excellent isolated yield of compound 8c results from its low
solubility in the reaction mixture, a typical feature in most
purines incorporating the 9-(4Ј-cyanophenyl) substituent.
Refluxing 2b in methanol/DBU (catalytic amount) gave only
compound 5b, isolated in 88% yield after 10 hours; there was no
evidence for the 6-methoxypurine 7b. Considering that the dif-
ference in boiling point between these two solvents (methanol,
bp 65 ЊC, ethanol, bp 78 ЊC) might be responsible for the differ-
ent reactivity of 2b in each solvent, a 1 : 8 mixture of methanol :
acetonitrile was used, in order to adjust the boiling point of the
solvent mixture to a value close to 78 ЊC. Under these experi-
mental conditions, the evolution of 2b occurred to give 7b in
76% yield, after refluxing the mixture for 25 hours. Similar sol-
vent mixtures were prepared for the reaction of 2a and 2c with
methanol, under reflux conditions, which again led to products
7a (84%) and 7c (97%). The high solubility of 6-methoxypurine
7b in the solvent mixture may again be responsible for the com-
paratively low isolated yield of this product, considering that
no other by-products were detected by TLC. The use of a
catalytic amount of DBU in the reactions with methanol (lead-
ing to 7a–c) may also account for the slightly higher isolated
yields of these products, when compared with the corre-
sponding reactions to form 8a–c, where one equivalent of DBU
was always used.
The reaction of 6-cyanopurines with methanol or ethanol
leads to 6-alkoxyformimidoylpurines 5 and 6 as the kinetic
products and to 6-alkoxypurines 7 and 8 under reflux condi-
tions. Consequently, the formation of the 6-alkoxypurine could
occur either from a 6-alkoxyformimidoylpurine or directly from
the 6-cyanopurine used as the starting material. In order to
understand the reaction mechanism, 6-(methoxyformimidoyl)-
9-(4Ј-cyanophenyl)purine 5c was reacted with ethanol and
methanol under the same reaction conditions as those
employed for the reaction with 6-cyanopurines (Scheme 3).
When compound 5c was refluxed in ethanol, in the presence
of one equivalent of DBU, no 6-ethoxypurine was detected on
TLC after 40 min. After 3 h under reflux conditions, only traces
of the 6-ethoxypurine were present in the reaction mixture.
Purine 8c was the major product in solution when the reflux
was carried out for 27 h. A much faster reaction occurred when
6-cyanopurine 2c was refluxed in ethanol/DBU, as the isolated
yield of 8c was 82% after 40 min. This result indicates that,
although the 6-methoxyformimidate group in 5c can be
replaced by the ethoxy group, the substitution of the 6-cyano
group is faster and must be the preferred pathway when 2c is
used as the starting material for this reaction.
5c
6c
7a
7b
7c
8a
8b
4-CNC6H4
4-CNC6H4
Me
4-MeOC6H4
4-CNC6H4
Me
97
a
84
76
97
48
46
4-MeOC6H4
8c
4-CNC6H4
82
a The solid isolated is a mixture of 6c and 8c in a 1 : 1 ratio.
nucleophiles as the reactions lead invariably to pyrimido[5,4-d]-
pyrimidine rearrangement products 4.1,20–23 Previous reports
on the reactions of 6-cyanopurines with amines are confus-
ing in that some authors report nucleophilic attack on the
cyano group24 while others suggest that treatment with meth-
anolic ammonia results in attack at the imidazole ring with
rearrangement to give a pyrimido[5,4-d]pyrimidine in unspeci-
fied yield20–22,25,26 or 17% yield.23 When this reaction is per-
formed in a pressure vessel at 0–18 ЊC, the reported yield of
rearranged product raises to 75%.27
These results throw into question the reports that 6-carb-
oxamidinopurine derivatives can be prepared from 6-cyano-
purines by direct reaction with ammonia or amine nucleophiles.
The use of a 6-alkoxyformimidoylpurine as the starting
material in the reaction with amines may solve this particular
problem, leading selectively to the formation of the amidine
function.28
Results and discussion
When a suspension of the 6-cyano-9-substituted purines 2a–c
in methanol was stirred at room temperature, in the presence of
a catalytic amount of DBU, nucleophilic attack of the solvent
occurred selectively on the cyano carbon atom and the corre-
sponding 6-(methoxyformimidoyl)purines 5a–c were isolated in
excellent yields (Scheme 2; Table 1). A similar reaction has been
reported previously by Rao and Revankar29 using concentrated
ammonia as the base. According to this reference, six differ-
ent 9-alkyl-6-cyanopurines were combined with a large excess
of aqueous ammonia and methanol, at room temperature,
and only one of these compounds led to the isolation of a
6-(methoxyformimidoyl)purine in 59% yield.
Scheme 2
When the 6-(methoxyformimidoyl)-9-(4Ј-cyanophenyl)-
purine 5c was refluxed in methanol/acetonitrile (8 : 1) in the
presence of a catalytic amount of DBU, the 6-methoxypurine
7c was formed as the only product after 20 h. This reaction time
compares with that registered for the preparation of 7c from the
The reaction of 6-cyano-9-substituted purines 2a–c was also
carried out in ethanol, but in this case TLC on the reaction
mixture indicated that a considerable amount of starting
material was still present after 5 days at room temperature. In
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 1 9 – 1 0 2 4
1020

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Scheme 3 Reagents and conditions: a) MeOH; b) EtOH.
Scheme 4 Reagents and conditions: a) NH2Me (aq), MeOH, rt, 3a (98%), 4b (86%), 4c (detected as the major component of the crude product, by 1H
NMR); b) NH2Me.HCl, CH2Cl2/MeOH, 1 : 1, 3b (isolated as the hydrochloride 86%), 3c (isolated as the hydrochloride, 92%).
6-cyanopurine 2c, under similar reaction conditions (17 h). No
traces of the 6-(methoxyformimidoyl)purine were detected by
TLC on the reaction mixture, but in this case the comparable
reaction time does not exclude the possibility of having both
pathways occurring simultaneously.
alkoxy group. No N–H signals could be detected both in the IR
and 1H NMR spectra. The high chemical shifts for C-2(H) and
C-8(H) (δ 8.3–9.0 ppm) are also typical of the purine ring
system.
The 6-alkoxyformimidoylpurines 5a–c were reacted with
aqueous methylamine (7 equivalents) in methanol (Scheme 4).
The 9-methylpurine 5a led exclusively to the corresponding
6-(N-methylamidino)purine 3a, isolated in 98% yield after 4
hours at room temperature and 14 hours at 4 ЊC. The reaction
with 9-arylpurines 5b and 5c led to the pyrimido[5,4-d]pyrim-
idines 4b (86% after 18 days at room temperature) and 4c
A detailed spectroscopic analysis was carried out for the
6-alkoxyformimidoylpurines 5 and for the 6-alkoxypurines 7
and 8. In the 6-alkoxyformimidoylpurines 5, the absence of the
cyano group is evident both in the IR spectrum and by 13C
NMR spectroscopy. The 13C NMR spectrum shows, in addi-
tion, the signal for the imidate carbon atom around δ 164 ppm,
as expected. The chemical shift for C-6 of the purine ring is
identified in the δ 143–149 ppm region, in contrast with the
corresponding signal for 6-cyanopurines, around δ 135 ppm.
No major changes occur in the position of the remaining
signals, indicating that the purine structure is clearly present.
1
(detected in the complex reaction mixture by H NMR on the
crude product).
Under these reaction conditions, nucleophilic attack on C-8
of the purine ring in 9-arylpurines, is a favoured process
compared to nucleophilic attack on the imidate function, lead-
ing to the pyrimido[5,4-d]pyrimidine rearrangement product 4
(Scheme 5).
1
This is supported by the H NMR chemical shifts for C-2(H)
and C-8(H), usually slightly higher than δ 9.0 ppm. A single
N–H signal is registered around δ 9.9 ppm, which reflects its
highly acidic character. This signal is sharp, suggesting that a
strong intramolecular H-bond maintains this proton in the
vicinity of N-7, in DMSO-d6 solution. This hydrogen bridge
seems to be present also in the solid state, as a single sharp
band around 3280 cmϪ1 is present in the spectra of all the
compounds. A strong band in the 1630–1635 cmϪ1 region is also
typical of these compounds. Compound 6c was very insoluble
in DMSO-d6 and the 1H NMR spectrum could only be
obtained when 5 µl of trifluoroacetic acid were added to 500 µl
of DMSO. Although the N–H signal is not observed in this
spectrum, the signals for the remaining protons are very similar
to those registered for the analogous compound 5c, which was
fully characterized.
In order to assist the elimination of alcohol from the imidate
function in the 6-position of purines 5b and 5c, after nucleo-
philic attack by the amine, the reactions were carried out using
methyl ammonium chloride (1 equivalent). Methanol and
dichloromethane (1 : 1 mixture) were used as solvents, and
reflux led to the formation of 6-carboxamidinopurines 3b (86%
after 2 hours) and 3c (96% after 5 hours). When the corre-
sponding 6-cyanopurines 2b and 2c were combined with methyl
ammonium chloride (1.2 equivalents) under similar reaction
conditions, only the starting material was isolated after reflux-
ing the reaction mixture for 26 hours (2b, 87%) and 14 hours
(2c, 84%). Previous work on the reaction of 6-cyanopurines 2b
and 2c with aqueous methylamine indicates that pyrimido-
[5,4-d]pyrimidines 4 are the only products isolated in this
process.1
For the 6-alkoxypurines 7 and 8, the 13C NMR spectrum
indicates that the purine skeleton is still present, with all the
signals in the expected positions. This includes C-6, around
δ 160 ppm, a chemical shift that reflects the influence of the
The synthesis of 9-aryl-6-(N-methylamidino)purines is a
delicate process and could only be achieved when the exocyclic
cyano group of the 9-aryl-6-cyanopurine was transformed into
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 1 9 – 1 0 2 4
1021

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Scheme 5
a 6-alkoxyformimidoyl group. Addition of the amine nucleo-
phile as the hydrochloride salt displaces the alkoxy group
leading to the desired product.
24.73%); νmax/cmϪ1 (Nujol mull) 3288s (NH), 1637s (C᎐N,
᎐
C᎐C), 1610, 1586, 1574; δ (300 MHz; (CD3)2SO; Me4Si) 9.88
᎐
H
(1 H, s, NH), 9.07 (1 H, s, H8), 9.05 (1 H, s, H2), 7.77 (2 H, d,
J 9.0, Hm), 7.17 (2 H, d, J 9.0, Ho), 3.95 (3 H, s, OCH3), 3.84
(3 H, s, OCH3); δC (75 MHz; (CD3)2SO; Me4Si) 164.2 (C10),
159.0 (Cp), 153.0 (C4), 151.8 (C2), 147.3 (C8), 144.3 (C6), 130.8
(C5), 126.7 (Ci), 125.3 (Co), 114.6 (Cm), 55.5 (OCH3), 53.1
(OCH3); m/z (FAB, 70 eV) 284 (M ϩ H)ϩ, 269 (M ϩ H Ϫ Me)ϩ.
Conclusion
The reaction of 6-cyanopurines with primary alcohols can
occur selectively on the carbon atom of the cyano substituent,
leading to 6-alkoxyformimidoylpurines 5 and 6 or on C-6 of the
purine ring, with nucleophilic substitution of either the cyano
or the alkoxyformimidoyl groups to give compounds 7 and 8.
Mild reaction conditions are required and the predominant
pathway depends on the temperature. Nucleophilic substitution
involves higher energy barriers and occurs when the temper-
ature value reaches 78 ЊC. Addition to the 6-cyano substituent
is kinetically controlled and occurs at room temperature. The
presence of DBU was essential in both cases and the reaction is
equally smooth from 9-methyl or 9-aryl-6-cyanopurines, where
the aryl group is substituted by either electron-donating (OMe)
or electron-withdrawing (CN) groups.
The 6-alkoxyformimidoylpurine 5a reacts with methylamine
and 5b and 5c react with methyl ammonium chloride leading to
6-(N-methylamidino)purines 3 in excellent yields. This repre-
sents the first general procedure for the synthesis of this type of
6-substituted purines and application of this method to other
nucleophiles is currently in progress.
9-(4Ј-Cyanophenyl)-6-(methoxyformimidoyl)purine (5c)
Yield: 97% (2.47 mmol); mp = 253–254 ЊC, dec; (Found: C
60.48; H 3.37; N 30.28. Calc. for C14H10N6O: C 60.43; H 3.60; N
30.22%); νmax/cmϪ1 (Nujol mull) 3255s (NH), 2227s (CN), 1635s
(C᎐N, C᎐C), 1611, 1586, 1568; δ (300 MHz; (CD ) SO; Me Si)
᎐
᎐
H
3
2
4
9.85 (1 H, s, NH), 9.31 (1 H, s, H8), 9.12 (1 H, s, H2), 8.24
(2 H, d, J 8.7, Hm), 8.16 (2 H, d, J 8.7, Ho), 3.95 (3 H, s, OCH3);
δC (75 MHz; (CD3)2SO; Me4Si) 164.3 (C10), 153.0 (C4), 152.2
(C2), 148.8 (C6), 146.7 (C8), 137.8 (Ci), 133.8 (Cm), 123.9 (Co),
123.4 (C5), 118.1 (CN), 110.7 (Cp), 53.3 (OCH3); m/z (FAB MS,
70 eV) 279 (M ϩ H)ϩ.
Synthesis of 9-(4Ј-methoxyphenyl)-6-(methoxyformimidoyl)-
purine 5b using reflux conditions
A suspension of 6-cyano-9-(methoxyphenyl)purine (0.08 g,
0.32 mmol) in methanol (2 cm3) in the presence of DBU (20 µl)
was refluxed for 10 h. An off-white solid was formed on cool-
ing and the suspension was filtered and washed with diethyl
ether (0.05 g). The mother liquor was concentrated on the
rotary evaporator leading to a second crop of the same product
(0.02 g). The two crops were combined and identified as the title
compound (0.07 g, 0.25 mmol, 88%).
Experimental
IR spectra were recorded on a Perkin-Elmer 1600 series FTIR
spectrometer, 1H and 13C NMR spectra on a Varian Unity Plus
spectrometer. Mass spectra were recorded on a GC-MS
Automass 120 or on a Kratos Concept instrument.
Synthesis of 9-(4Ј-cyanophenyl)-6-(ethoxyformimidoyl)purine
(6c)
General procedure for the synthesis of 6-(methoxyformimidoyl)-
purines (5)
A suspension of 6-cyano-9-(4Ј-cyanophenyl)purine (0.18 g,
0.72 mmol) in ethanol (5 cm3) was stirred at room temperature
in the presence of DBU (110 µl, 0.72 mmol). The reaction mix-
ture was stirred for 13 days, when TLC indicated that all the
starting material had been consumed. The solid suspension was
filtered and washed with ethanol followed by diethyl ether. The
1H NMR spectrum on the solid showed that it was a mixture of
the 9-(4Ј-cyanophenyl)-6-ethoxypurine 6c and 9-(4Ј-cyano-
phenyl)-6-(ethoxyformimidoyl)purine 8c in a 1 : 1 ratio (0.16 g).
δH (300 MHz; (CD3)2SO ϩ CF3CO2D, 100 : 1; Me4Si) for 6c
9.28 (1 H, s, H8), 9.14 (1 H, s, H2), 8.23 (2 H, d, J 8.7, Hm), 8.10
(2 H, d, J 8.7, Ho), 3.47 (2 H, q, J 7.2, OCH2), 1.38 (3 H, t, J 7.2,
CH3).
A suspension of 6-cyanopurine 2 in methanol and DBU (20 µl,
0.05–0.06 molar equivalents) was stirred efficiently at room
temperature. The reaction was followed by TLC until the start-
ing material was no longer present; the white solid was filtered
and washed with ethanol followed by diethyl ether. A second
crop of the same product could usually be recovered from the
mother liquor after concentration on the rotary evaporator.
9-Methyl-6-(methoxyformimidoyl)purine (5a)
Yield: 94% (1.59 mmol); mp = 175–177 ЊC dec; (Found: C
50.07; H 4.83; N 36.44. Calc. for C8H9N5O: C 50.26; H 4.71; N
36.65%); νmax/cmϪ1 (Nujol mull) 3278s (NH), 1635 (C᎐C, C᎐N),
᎐
᎐
1587s; δH (300 MHz; (CD3)2SO; Me4Si) 9.83 (1 H, s, NH), 9.00
(1 H, s, H2), 8.72 (1 H, s, H8), 3.91 (3 H, s, OCH3), 3.87 (3 H, s,
NCH3); δC (75 MHz; (CD3)2SO; Me4Si) 164.4 (C10), 153.7 (C4),
151.3 (C2), 149.1 (C8), 143.4 (C6), 130.5 (C5), 53.2 (OCH3), 29.8
(NCH3); m/z (FAB, 70 eV) 192 (M ϩ H)ϩ.
General procedure for the synthesis of 6-methoxypurines (7)
A solution of 6-cyanopurine 2 in a mixture of acetonitrile :
methanol in an 8 : 1 ratio, was heated to reflux temperature.
DBU (40 µl, 0.3–0.6 molar equivalents) was added and the mix-
ture was refluxed until no starting material was present accord-
ing to TLC. The orange solution was filtered through glass-fibre
paper in order to eliminate dark residues in suspension. The
mother liquor was concentrated to a yellow solid in the rotary
evaporator. Addition of ethanol followed by diethyl ether led to
9-(4Ј-Methoxyphenyl)-6-(methoxyformimidoyl)purine (5b)
Yield: 96% (0.34 mmol); mp = 201–203 ЊC; (Found: C 59.38, H
4.68, N 24.91. Calc. for C14H13N5O2: C 59.36, H 4.59, N
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 1 9 – 1 0 2 4
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a yellow solid suspension that was filtered and washed with
6-Ethoxy-9-(4Ј-methoxyphenyl)purine (8b)
diethyl ether.
Yield: 46% (0.37 mmol); mp = 169–172 ЊC; (Found: C 62.08; H
5.31; N 20.79. Calc. for C14H14N4O2: C 62.22; H 5.19; N
20.74%); νmax/cmϪ1 (Nujol mull) 1604s (C᎐N, C᎐C), 1569, 1524;
9-(4Ј-Methoxyphenyl)-6-methoxypurine (7b)
᎐
᎐
Yield: 76% (2.09 mmol); mp = 149–150 ЊC; (Found: C 60.85; H
4.90; N 22.02. Calc. for C13H12N4O2: C 60.94; H 4.69; N
21.88%); νmax/cmϪ1 (Nujol mull) 1617s (C᎐N, C᎐C), 1602, 1567;
δH (300 MHz; (CD3)2SO; Me4Si) 8.70 (1 H, s, H8), 8.57 (1 H, s,
H2), 7.75 (2 H, d, J 9.0, Hm), 7.15 (2H, d, J 9.0, Ho), 4.12 (3 H, s,
OCH3), 3.83 (3 H, s, OCH3); δC (75 MHz; (CD3)2SO; Me4Si)
160.5 (C6), 158.8 (Cp), 152.0 (C2), 151.6 (C4), 142.8 (C8), 127.4
(Ci), 125.5 (C5), 125.0 (Co), 114.6 (Cm), 55.5 (OCH3), 54.0
(OCH3).
δH (300 MHz; (CD3)2SO; Me4Si) 8.69 (1 H, s), 8.54 (1 H, s), 7.73
(2 H, d, J 8.7), 7.14 (2 H, d, J 8.7), 4.61 (2 H, q, J 6.9), 3.82 (3 H,
s), 1.42 (3 H, t, J 6.9); δC (75 MHz; (CD3)2SO; Me4Si) 160.2,
158.7, 151.9, 151.6, 142.5, 127.4, 125.2, 124.9, 114.6, 62.5, 55.4,
14.3.
᎐
᎐
9-(4Ј-Cyanophenyl)-6-ethoxypurine (8c)
Yield: 82% (1.14 mmol); mp above 222 ЊC, dec; (Found: C
63.14; H 4.35; N 26.16. Calc. for C14H11N5O: C 63.40; H 4.15; N
26.42%); νmax/cmϪ1 (Nujol mull) 2227m (CN), 1596s (C᎐N,
᎐
9-(4Ј-Cyanophenyl)-6-methoxypurine (7c)
C᎐C), 1518; δ (300 MHz; (CD3)2SO; Me4Si) 8.96 (1 H, s,
᎐
H
Yield: 97% (0.81 mmol); mp above 300 ЊC, dec; (Found: C
H8), 8.61 (1 H, s, H2), 8.24 (2 H, d, J 9.0, Hm), 8.11 (2 H, d,
J 9.0, Ho), 4.63 (2 H, q, J 7.2, OCH2), 1.43 (3 H, t, J 7.2, CH3);
δC (75 MHz; (CD3)2SO; Me4Si) 160.4 (C6), 152.5 (C2), 151.5
(C4), 142.2 (C8), 138.5 (Ci), 133.9 (Cm), 123.2 (Co), 121.5 (C5),
118.3 (CN), 110.1 (Cp), 62.9 (OCH2), 14.4 (CH3).
61.91; H 3.80; N 28.17. Calc. for C13H9N5O: C 62.15; H 3.59;
N 27.89%); νmax/cmϪ1 (Nujol mull) 2230m (CN), 1614s (C᎐N,
᎐
C᎐C), 1599, 1564; δ (300 MHz; (CD ) SO; Me Si) 8.96 (1 H, s,
᎐
H
3
2
4
H8), 8.65 (1 H, s, H2), 8.24 (2 H, d, J 9.0, Ho), 8.12 (2 H, d, J 9.0,
Hm), 4.14 (3 H, s, OCH3); δC (75 MHz; (CD3)2SO; Me4Si) 160.7
(C6), 152.5 (C2), 151.4 (C4), 142.3 (C8), 138.4 (Ci), 133.9 (Cm),
123.3 (Co), 121.6 (C5), 118.3 (CN), 110.1 (Cp), 54.2 (OCH3).
Reaction of 9-(4Ј-cyanophenyl)-6-(methoxyformimidoyl)purine
5c with methanol
Synthesis of 9-methyl-6-methoxypurine (7a)
A suspension of 6-(methoxyformimidoyl)-9-(4Ј-cyanophenyl)-
purine 5c (0.10 g, 0.37 mmol) in acetonitrile : methanol, 8 : 1
(9 cm3) was refluxed and the reaction was followed by TLC.
After 20 h, the starting material was no longer present on TLC
and the yellow solid was filtered and washed with ethanol fol-
lowed by diethyl ether (0.07 g). A second crop was obtained
from the mother liquor (0.01 g). The two crops were identical by
TLC and were combined and identified as the 6-methoxypurine
A solution of 6-cyano-9-methylpurine (0.14 g, 0.89 mmol) in
acetonitrile (16 cm3) with a catalytic amount of DBU (40 µl)
was kept under reflux conditions, when methanol (2 cm3) was
added dropwise. The mixture was refluxed for three days, when
the starting material was no longer detected by TLC. The
solvent mixture was completely removed in the rotary evapor-
ator leading to an oil. The oil was solubilized in acetonitrile and
filtered through a short column (0.2 × 3 cm) of Kieselgel 60 for
column chromatography (particle size less than 0.063 mm),
which was than eluted with ethyl acetate (200 cm3). The solvent
was removed in the rotary evaporator leading to a cream solid.
Petroleum ether was added to the solid, which was filtered
and washed with petroleum ether. The product was identified as
the purine 7a (0.12 g, 0.75 mmol, 84%); mp = 141–142 ЊC, dec;
νmax/cmϪ1 (Nujol mull) 1606s (C᎐N, C᎐C), 1577; δH (300 MHz;
1
7c (0.08 g, 0.32 mmol, 86.5%) by comparison of the H NMR
spectrum with that of an authentic sample.
Reaction of 9-(4Ј-cyanophenyl)-6-(methoxyformimidoyl)purine
5c with ethanol
A suspension of 6-(methoxyformimidoyl)-9-(4Ј-cyanophenyl)-
purine 5c (0.10 g, 0.37 mmol) in ethanol (10 cm3) was refluxed
and the reaction was followed by TLC. After 3 h, the presence
of 6-ethoxypurine could be detected on TLC and no starting
material was present after 27 h. The yellow solid was filtered
and washed with ethanol followed by diethyl ether giving 0.04 g
of product. Two other crops were recovered from the mother
liquor (0.02 g and 0.01 g). The three crops were identical by
TLC and were combined and identified as the 6-ethoxypurine
᎐
᎐
(CD3)2SO; Me4Si) 8.52 (1 H, s, H2), 8.32 (1 H, s, H8), 4.08 (3 H,
s, OCH3), 3.80 (3 H, s, NCH3); δC (75 MHz; (CD3)2SO; Me4Si)
160.1, 152.4, 151.4, 144.3, 120.4, 53.8, 29.7; MS (FAB) m/z (rel
int) 165 (M ϩ 1, 100). HRMS (FAB) m/z (FAB) 165.078425
((M ϩ H)ϩ. C7H8N4O requires 165.077636).
1
General procedure for the synthesis of 6-ethoxypurines (8)
8c (0.07 g, 0.27 mmol, 73%) by comparison of the H NMR
spectrum with that of an authentic sample.
A suspension of 6-cyanopurine 2 in ethanol and DBU (1 molar
equivalent) was refluxed until no starting material was detected
by TLC. A homogeneous orange solution was obtained and the
solvent was concentrated in the rotary evaporator. Compounds
8b and 8c precipitate from the reaction mixture and were fil-
tered and washed with diethyl ether, leading to yellow solids.
For compound 8a, an oil was obtained which was supported on
silica and submitted to dry flash chromatography. The pure
compound 8a was isolated as a yellow solid using diethyl ether
as eluant. The solid was filtered and washed with a mixture of
diethyl ether/pet. ether 40–60.
Reaction of 9-methyl-6-(methoxyformimidoyl)purine 5a with
methylamine
Aqueous methylamine (0.8 cm3 of a 40% aqueous solution, 9.24
mmol) was added to a suspension of 9-methyl-6-(methoxy-
formimidoyl)purine 5a (0.25 g, 1.32 mmol) in methanol (5 cm3),
and the mixture was stirred at room temperature in a round-
bottom flask equipped with a serum cap. After 4 h at room
temperature, the reaction was stirred at 4 ЊC for another 14 h
and the homogeneous solution was concentrated in the rotary
evaporator. Addition of cold diethyl ether led to a suspen-
sion which was filtered and washed abundantly with diethyl
ether. The white solid was identified as 9-methyl-6-(N-methyl-
amidino)purine 3a (0.25g, 1.30 mmol, 98%), mp = 105–107 ЊC;
(Found: C 42.42; H 6.16; N 36.98. Calc. for C8H10N6.2H2O: C
42.67; H 6.22; N 37.33%); νmax/cmϪ1 (Nujol mull) 3481s (NH),
3354s (NH), 3324s (NH), 3171s (NH), 3052s (NH), 1513m,
1581s; δH (300 MHz; (CD3)2SO; Me4Si) 9.01 (1 H, s, H8), 8.74
(1 H, s, H2), 7.50 (1 H, br s, NH), 7.46 (1 H, br s, NH), 3.88
(3 H, s, N9CH3), 2.93 (3 H, s, NCH3); δC (75 MHz; (CD3)2SO;
6-Ethoxy-9-methylpurine (8a)
Yield: 48% (0.47 mmol); mp = 112–114 ЊC; (Found: C 53.93;
H 5.72; N 31.25. Calc. for C8H10N4O: C 53.93; H 5.62; N
31.46%); νmax/cmϪ1 (Nujol mull) 1619m (C᎐N, C᎐C), 1600,
᎐
᎐
1582; δH (300 MHz; (CD3)2SO; Me4Si) 8.50 (1 H, s, H2), 8.31
(1 H, s, H8), 4.57 (2 H, q, J 6.9, OCH2), 3.79 (3 H, s, N9CH3),
1.39 (3 H, t, J 6.9, CH3); δC (75 MHz; (CD3)2SO; Me4Si) 159.8
(C6), 152.4 (C4), 151.4 (C2), 144.2 (C8), 120.4 (C5), 62.4 (OCH2),
29.7 (N9CH3), 14.4 (CH3).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 1 9 – 1 0 2 4
1023

View Article Online
Me4Si) 158.5 (CAm), 153.5 (C3), 151.1 (C2), 148.9 (C8), 143.7
(C6), 129.8 (C5), 29.9 (N9CH3), 28.1 (NAmCH3).
(2c). The solid material precipitated on cooling and was filtered
and washed with methanol followed by diethyl ether. The prod-
uct was identified as the 6-cyanopurine 2b (0.11 g, 0.43 mmol,
84%) or 2c (0.15 g, 0.61 mmol, 87%).
Reaction of 9-aryl-6-(methoxyformimidoyl)purines 5b and 5c
with methylamine
Aqueous methylamine (7 molar equivalents of a 40% aqueous
solution) was added to a suspension of 9-aryl-6-(methoxy-
formimidoyl)purine (0.20 g, 0.72 mmol for 5b and 0.22 g,
0.80 mmol for 5c) in methanol (5 cm3), and the mixture was
stirred at room temperature in a round-bottom flask equipped
with a serum cap. The reaction was followed by TLC and the
product was isolated when the starting material was no longer
present. The solid suspension was filtered and washed with
diethyl ether. A white solid was isolated from the reaction of 5b
and was identified as the pyrimido[5,4-d]pyrimidine 4b (0.17 g,
Acknowledgments
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).
References
1 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 Trans. 1, 2001, 2532.
1
0.62 mmol, 86%), by comparison of the H NMR spectrum
2 J. H. Lister, in The Chemistry of Heterocyclic Compounds, vol 24 (II);
Fused Pyrimidines, Part II, Purines; ed. E. C. Taylor and
A. Weissberger, Wiley-Interscience, New York, 1971, pp. 380–382.
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with the data described in the literature for an authentic
sample.1 A pale yellow solid was isolated from the reaction of
1
5c and H NMR indicated that the pyrimido[5,4-d]pyrimidine
4c was the major component in the mixture, by comparison
with the data described in the literature.1
General procedure for the reaction of 9-aryl-6-
(methoxyformimidoyl)purines 5b and 5c with methyl ammonium
chloride
5 L. B. Mackay and G. H. Hitchings, J. Am. Chem. Soc., 1956, 78,
3511.
6 M. Hocek, M. Masojidkova, A. Holy, A. Graciela, R. Snoeck,
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A solution of methyl ammonium chloride (1 molar equivalent)
in methanol (5 cm3) was combined with a suspension of 9-aryl-
6-(methoxyformimidoyl)purine in dichloromethane (5 cm3).
The mixture was refluxed until no starting material was
detected by TLC (2 h for purine 5b and 6 h for purine 5c). The
solution was concentrated in the rotary evaporator. Addition of
ethanol followed by diethyl ether led to a solid which was fil-
tered and washed with diethyl ether. Two crops of the same
product were isolated and combined. The product was identi-
fied as the hydrochloride of 9-aryl-6-(N-methylamidino)purine
(3b, 0.20 g, 0.64 mmol, 86% and 3c, 0.08 g, 0.24 mmol, 92%).
7 J. H. Lister, in The Chemistry of Heterocyclic Compounds, vol 24 (II),
Fused Pyrimidines, Part II, Purines, ed. E. C. Taylor and
A. Weissberger, Wiley-Interscience, New York, 1971, pp. 203–309.
8 J. H. Lister, in The Chemistry of Heterocyclic Compounds, vol 54,
The Purines, Supplement 1, ed. E. C. Taylor and A. Weissberger,
Wiley-Interscience, New York, 1996, pp. 133–179.
9 A. Yamane, A. Matsuda and T. Ueda, Chem. Pharm. Bull., 1980, 28,
150.
10 R. J. Badger and G. B. Barlin, J. Chem. Soc., Perkin Trans. 1, 1976,
151.
11 R. J. Badger and G. B. Barlin, J. Chem. Soc., Perkin Trans. 2, 1976,
1176.
12 M. Hori, T. Kataoka, H. Shimizu, M. Yokomoto and Y. Ando,
Synthesis, 1987, 278.
13 G. H. Milne and B. L. Townsend, J. Chem. Soc., Perkin Trans. 1,
1973, 313.
9-(4Ј-Methoxyphenyl)-6-(N-methylamidino)purine hydrochloride
(3b)
14 G. H. Milne and B. L. Townsend, J. Med. Chem., 1974, 17, 263.
15 V. Samano, R. W. Miles and M. J. Robins, J. Am. Chem. Soc., 1994,
116, 9331.
16 G. B. Barlin and A. C. Young, J. Chem. Soc., Perkin Trans. 1, 1972,
1269.
17 J. A. Linn, E. W. McLean and J. L. Kelly, J. Chem. Soc.,
Chem. Commun., 1994, 913.
18 R. W. Adamiak, E. Biala and B. Skalski, Angew. Chem., Int. Ed.
Engl., 1985, 24, 1054.
Mp 271–273 ЊC; (Found: C 48.83; H 5.23; N 24.21. Calc. for
C14H14N6O.HCl.1.5H2O: C 48.63; H 5.21; N 24.31%); νmax/cmϪ1
(Nujol mull) 3320m, 1677s, 1593s, 1523s; δH (300 MHz;
(CD3)2SO; Me4Si) 10.2 (2 H, br s, NH), 9.38 (1 H, s, H8), 9.23
(1 H, s, H2), 7.80 (2 H, d, J 9.0, Hm), 7.20 (2 H, d, J 9.0, Ho),
3.84 (3 H, s, OCH3), 3.23 (3 H, s, CH3); δC (75 MHz; (CD3)2SO;
Me4Si) 159.4 (Cp), 157.8 (CAm), 153.4 (C4), 152.1 (C2), 149.3
(C8), 140.3 (C6), 131.3 (C5), 126.3 (Ci), 125.6 (Co), 114.9 (Cm),
55.7 (OCH3), 30.1 (NCH3).
19 L. Y. Zhn, X. T. Liang and T. S. Lin, J. Chin. Chem. Lett., 1991, 2,
601.
20 P. C. Srivastava, G. Revankar and R. K. Robins, J. Med. Chem.,
1981, 24, 393.
21 H. M. Berman, R. J. Rousseau, R. W. Mancuso, G. P. Kreishman
and R. K. Robins, Tetrahedron Lett., 1973, 33, 3099.
22 J. D. Westover, G. R. Revankar, R. K. Robins, R. D. Madsen,
R. D. Ogden, J. R. North, R. W. Mancuso, R. J. Rousseau and
E. L. Stephan, J. Med. Chem., 1981, 24, 941.
23 T. E. Mabry, C. D. Jones, T. S. Chou, J. M. Colacino, G. B. Grinday,
J. F. Worzallan and H. L. Pearce, Nucleosides Nucleotides, 1994, 13,
1125.
24 T. Higashino, S. Yoshida and E. Hayashi, Chem. Pharm. Bull., 1982,
30, 4521.
9-(4Ј-Cyanoyphenyl)-6-(N-methylamidino)purine hydrochloride
(3c)
Mp 230–232 ЊC, dec; νmax/cmϪ1 (Nujol mull) 3370s, 2234m
(CN), 1693m, 1651m, 1591s; δH (300 MHz; (CD3)2SO; Me4Si)
10.15 (2 H, br s, NH), 9.8 (1 H, br s, NH), 9.61 (1 H, s, H8), 9.32
(1 H, s, H2), 8.28 (2 H, d, J 8.4, Hm), 8.19 (2 H, d, J 8.4, Ho),
3.22 (3 H, s, NCH3); δC (75 MHz; (CD3)2SO; Me4Si) 157.6
(CAm), 153.2 (C4), 152.4 (C2), 148.7 (C8), 140.8 (C6), 137.5 (Ci),
134.0 (Cm), 131.7 (C5), 124.0 (Co) 118.2 (CN), 111.0 (Cp), 30.1
(NCH3). MS (FAB) m/z (rel int) 278 (M ϩ 1, 100). HRMS
(FAB) m/z (FAB) 278.1165 ((M ϩ H)ϩ. C14H11N7 requires
278.1154).
25 P. Narayanan and H. M. Berman, Carbohydr. Res., 1975, 44, 169.
26 Y. S. Sanghvi, S. B. Larson, S. S. Matsumoto, L. D. Nord, D. F.
Smee, R. C. Willis, T. L. Avery, R. K. Robins and G. R. Revankar,
J. Med. Chem., 1989, 32, 629.
27 P. D. Cook and D. A. Berry, Eur. Pat. Appl. EP 257,488/02 Mar,
1988; P. D. Cook and D. A. Berry, Chem. Abstr., 1988, 109, 110861h.
28 The Chemistry of Amidines and Imidates, ed. S. Patai and
Z. Rappoport, John Wiley & Sons, New York, 1991, vol 2, pp. 448–
452.
General procedure for the reaction of 9-aryl-6-cyanopurines 2b
and 2c with methyl ammonium chloride
A suspension of 9-aryl-6-cyanopurine and methyl ammonium
chloride (1.2 molar equivalents) in a 1 : 1 mixture of ethanol
and dichloromethane (10 cm3) was refluxed for 26 h (2b) or 14 h
29 T. S. Rao and G. Revankar, Nucleosides and Nucleotides, 1995, 14,
1601.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 1 9 – 1 0 2 4
1024