A new and efficient approach to the synthesis of 6-amidino-2-oxopurines

Article abstract of DOI:10.1039/b010224p

The reaction of 5-amino-4-cyanoformimidoylimidazoles 1a and 1b with tosyl isocyanate proved to be a mild and efficient method for the synthesis of the corresponding 6-amidino-2-oxopurines 5. These compounds, which were isolated in almost quantitative yield, rearrange in the presence of acetic acid-DMF to give a pyrimido[5,4-d]-pyrimidin-2-one 6. The structure of compound 6 was confirmed by X-ray crystallography. The pathway for both reactions is discussed. Studies on the reactivity of tosyl isocyanate with imidazoles 2, 7, 8 and 16, obtained from 1 by selective acylation of the amino or imino nitrogen atoms, enabled clarification of the mechanism for purine formation.

Full text of DOI:10.1039/b010224p

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A new and efficient approach to the synthesis of 6-amidino-2-
oxopurines
Brian L. Booth,a Isabel M. Cabral,b Alice M. Dias,b A. Paula Freitas,b Ana M. Matos Beja,c
M. Fernanda Proença*b and Manuela Ramos Silvac
1
a Department of Chemistry, UMIST, PO Box 88, Manchester, UK M60 1QD
b Centro de Química-IBQF, Universidade do Minho, Campus de Gualtar, 4710 Braga, Portugal
c CEMDRX, Departamento de Física, FCTUC, 3004-516, Coimbra, Portugal
Received (in Cambridge, UK) 21st December 2000, Accepted 4th April 2001
First published as an Advance Article on the web 3rd May 2001
The reaction of 5-amino-4-cyanoformimidoylimidazoles 1a and 1b with tosyl isocyanate proved to be a mild and
efficient method for the synthesis of the corresponding 6-amidino-2-oxopurines 5. These compounds, which were
isolated in almost quantitative yield, rearrange in the presence of acetic acid–DMF to give a pyrimido[5,4-d]-
pyrimidin-2-one 6. The structure of compound 6 was confirmed by X-ray crystallography. The pathway for both
reactions is discussed. Studies on the reactivity of tosyl isocyanate with imidazoles 2, 7, 8 and 16, obtained from 1
by selective acylation of the amino or imino nitrogen atoms, enabled clarification of the mechanism for purine
formation.
Introduction
Previous work in our research group has shown that 5-amino-4-
cyanoformimidoylimidazoles 1 are versatile precursors of
substituted purines. The reaction with ketones leads to 1,2-
dihydro-6-carboxamidopurines and with aldehydes to the
6-carboxamidopurines.1,2 In the presence of anhydrides, the 6-
cyanopurines are formed,3 and ethyl chloroformate leads to
6-cyano-2-oxopurines 3.4 We now describe the reaction of
imidazoles 1 with tosyl isocyanate, which proved to be a simple
and efficient method for the synthesis of 6-carboxamidino-2-
oxopurines. A literature survey indicates that only a limited
number of 6-carboxamidinopurines has been reported. These
compounds were prepared from N-substituted 6-cyanopurines
and 2-amino-6-cyanopurines, on treatment with a catalytic
amount of sodium methoxide in methanol, followed by addi-
tion of ammonium chloride.5 The same type of reaction was
claimed to occur from 9-phenyl-6-cyanopurines after refluxing
a methanolic or ethanolic solution of this compound with
hydrazine, hydroxylamine, n-butylamine and piperidine.6 The
N-substituted imidazole ring has also been introduced in the
6-position of a 6-iodopurine. This reaction requires the initial
formation of the imidazole anion (Li or Zn) at the 2-position,
which was then coupled with a 6-iodopurine using a catalytic
amount of Pd(0).7
Results and discussion
The reaction of imidazole 1 with a slight excess of tosyl iso-
cyanate was carried out under a nitrogen atmosphere. The
reagents were combined at 0 ЊC and the mixture was stirred at
room temperature for a few hours. The products 5a–e precipi-
tated from the reaction mixture as yellow solid materials and
were isolated by filtration in 85–99% yield (Scheme 1). This
reaction is always accompanied by rapid colour and texture
changes, which precede the formation of the final product. All
attempts to isolate and characterise the intermediates were
unsuccessful due to their instability in the solid state.
The reaction of imidazole 1 and tosyl isocyanate was previ-
ously investigated in our group and the product was initially
thought to have the imidazo[4,5-d][1,3]diazepine structure 4 on
the basis of elemental analysis and spectroscopic data, but
Scheme 1
this was subsequently shown by X-ray crystallography to be
incorrect. Attempts to obtain crystals proved difficult as the
compound was insoluble in most of the common organic
solvents. Only by using a mixture of glacial acetic acid and
DMF and allowing the solvent to evaporate slowly over a
period of at least 6 months were obtained yellow needle
crystals, suitable for X-ray analysis. Although this yellow solid
was different from the yellow starting material according to IR,
1H and 13C NMR data, both structures had the same empirical
formula, considering the elemental analysis results and that the
DOI: 10.1039/b010224p
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251
This journal is © The Royal Society of Chemistry 2001
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chemical shifts as those registered for the sample where no
acetic acid was incorporated.
The formation of the pyrimido[5,4-d]pyrimidine 6 can be
envisaged through the mechanism described in Scheme 2, by
Fig. 1 Ortep II14 plot of 4-(4Ј-methoxyphenyl)amino-8-(N-tosyl-
imino)-7,8-dihydropyrimido[5,4-d]pyrimidin-2(1H)-one 6. Displace-
ment ellipsoids are drawn at the 50% probability level.
crystals incorporated one equivalent of acetic acid and water.
The compound was identified as a pyrimido[5,4-d]pyrimidin-2-
one 6 (R = 4-MeOC6H4) by X-ray diffraction (Fig. 1). Analysis
of the X-ray data indicates that the tautomer which is present
in the solid state shows an exocyclic double bond linking the
toluene-p-sulfonamide substituent to the heterocyclic ring and
that the three tautomerisable hydrogen atoms are located on
N(2), N(4) and most likely N(6), although we cannot exclude
the possibility of a mixture of protonation sites between N(6)
and N(5). Bond length analysis suggests that there is no aro-
matic character of the fused pyrimido-pyrimidine ring due to
the high double bond character of C(10)–C(11) [1.344(9) Å]
and to the extended conjugation with the substituents on the
ring. This conjugation is predominantly affecting the bonds:
C(12)–N(5) [1.350(8) Å], N(5)–C(13) [1.320(8) Å] and C(13)–
N(6) [1.333(8) Å] and also one of the amidine units N(2)–C(8)
[1.339(9) Å] and C(8)–N(1) [1.318(8) Å]. The anisole ring is
slightly distorted with respect to the pyrimido-pyrimidine
system, which is mostly planar [torsion angles C(13)–N(6)–
Scheme 2
rearrangement of a 6-(N-tosylamidino)-2-oxopurine 5 upon
heating in the presence of any nucleophilic species. The struc-
ture of compound 5 is also supported by IR spectroscopy,
where an intense band in the 1640–1660 cmϪ1 region can be
assigned to the carbonyl stretching vibration. The stretching
vibrations of the amino group are also present in the 3300–3390
cmϪ1 region. In the 1H NMR, a one proton singlet at δ 8.4–9.0
ppm was assigned to the C(8)–H. The two protons of the amino
group are non-equivalent leading to two broad singlets, each
one integrating to less than one proton, around δ 8.7 and 9.2
ppm. This non-equivalence was attributed to conjugation
within the amidine substituent and to intramolecular hydrogen
bonding with the imidazole nitrogen. The 13C NMR spectrum
confirms the presence of the tosyl group in all the compounds.
The HMBC† technique was used for compound 5b, which
enabled the identification of C(8) at δ 146.0 ppm. The signals at
δ 155.8 and 126.2 ppm showed three-bond interactions with
C(8)H and were assigned respectively to C(4) and C(5). All the
carbon atoms of the tosyl and aryl groups were clearly identi-
fied with this technique, and the remaining carbon atoms could
be assigned with certainty to C(2), C(6) and C(10).
In order to clarify the mechanism for the reaction of imid-
azoles 1 with tosyl isocyanate and understand the first step in
the reaction sequence, both the amino and the imino nitrogen
atoms were selectively protected by acetylation. The reaction of
imidazoles 1 with acetic anhydride using acetonitrile as solvent,
was previously reported to cause N-acetylation in the 5-position
of the imidazole ring.8 A recent spectroscopic analysis using the
HMBC technique, indicates that the acetyl group is initially
located next to the imino nitrogen atom. Compound 7, isolated
as a yellow solid, is the kinetic product, and in ethanol solution
the acetyl migration leads to the thermodynamically more
stable structure 8, a white solid material (Scheme 3).
C(14)–C(19) = 173.1(6)Њ,
N(2)–C(8)–C(11)–N(4) = 177.2(5)Њ
andN(1)–C(8)–C(11)–C(10) = 176.3(6)Њ]. Intramolecularhydro-
gen bonding can be envisaged between N(4)H and N(1)
[2.743(7) Å], between N(6)H and N(3) [2.728(7) Å] and also
between N(2)H and O(1) [2.892(7) Å].
Further attempts to prepare compound 6 in a more conveni-
ent way included reflux for 15 h, of a solution of compound 5b
in glacial acetic acid and DMF. The pyrimido-pyrimidine 6 was
isolated in only 38% yield, as a greenish-yellow solid. When
ammonium acetate was added to a suspension of compound
5b in glacial acetic acid and the mixture was refluxed for 4 h,
the product precipitated on cooling and was isolated in 86%
yield. Neither solid incorporates acetic acid, as evidenced by
elemental analysis and spectroscopic data. The pyrimido-
[5,4-d]pyrimidin-2-one structure 6 shows a typical carbonyl
absorption in the IR spectrum at ν 1682 cmϪ1. In the 1H NMR
spectrum, besides the signals for the tosyl and the aryl groups, a
singlet at δ 8.26 ppm was assigned to the C–H proton. Only two
N–H signals were visible at δ 10.0 and 10.1 ppm as broad sing-
lets. In the 13C NMR, it is possible to identify all the signals for
the tosyl and aryl carbon atoms, but only four singlets are left
for the six carbon atoms of the pyrimido-pyrimidine ring. From
these, only the C–H could be assigned with certainty at δ 145.1
ppm. The three signals missing are likely to correspond to
C(4a), C(8) and C(8a). These signals, which would normally be
small, could disappear in the baseline due to ring tautomerism
in solution. The presence of one equivalent of acetic acid in the
crystals which were submitted for X-ray analysis was evident in
the IR spectrum, which showed two intense bands at ν 1709
(acid C᎐O) and 1644 cmϪ1 (ring C᎐O). In the 1H NMR
The spectroscopic characterisation of compounds 7a and 7b
shows the presence of an intense band in the IR spectrum at ν
1647 cmϪ1 (7a) and ν 1670 cmϪ1 (7b) respectively, which can be
assigned to the stretching vibration of the carbonyl group. The
stretching vibration of the cyano group is not visible in the
1
spectrum of either compound 7a or 7b. In the H NMR spec-
trum, the methyl group is a singlet at δ 2.2 ppm and the imid-
azole CH is also a singlet at δ 7.48 ppm (7a) and δ 7.66 ppm
(7b). The 13C NMR could be registered only for compound 7a
as in DMSO solution acetyl migration is a fast process for 7b,
᎐
᎐
spectrum, a singlet at δ 1.9 ppm, integrating for three protons,
was assigned to the methyl group of the acetic acid molecule. In
this sample, all the remaining signals showed exactly the same
† HMBC = heteronuclear multiple bond correlation.
1242
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251

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Scheme 3
leading to structure 8b. For 7a it is possible to identify the
δ 8.11 ppm (9b). The HMBC spectrum of 9e identifies C(2) at
cyano group at δ 112.5 ppm and the CH at δ 139.8 ppm. The
signal at δ 184.1 ppm was assigned to the carbonyl group. Using
the HMBC technique, it is possible to detect a four-bond inter-
action between the methyl hydrogens and C(6) (δ 132.5 ppm).
The three-bonds interaction between C(2)H, C(4) (δ 122.5 ppm)
and C(5) (δ 151.5 ppm), unequivocally identifies these signals.
For compounds 8, the cyano stretching vibration is present in
the IR spectrum as a weak signal at ν 2240 cmϪ1 (8a) and ν 2238
cmϪ1 (8b). The carbonyl stretching vibration is an intense band
at ν 1696 cmϪ1 (8a) and ν 1682 cmϪ1 (8b). Two sets of bands (A
and B) are visible for both compounds in the 1H and 13C NMR
spectra. This may be due either to tautomerism or to intra-
molecular hydrogen bonding, for which two possibilities can be
δ 139.4 ppm and, as a three-bonds interaction, C(4) at δ 127.3
ppm and C(5) at δ 132.0 ppm. The carbonyl of the acetyl group
could be identified at δ 182.2 ppm.
The ureido function in the 5-position of imidazoles 9 is very
sensitive to hydrolysis in DMSO solution. After two days at
room temperature, the starting material is no longer present.
1
When the decomposition of 9e is followed by H NMR, at
room temperature, the only compounds detected are toluene-
p-sulfonamide and 6-cyano-2-methylpurine 10e. From 9b,
toluene-p-sulfonamide is also formed, together with a 1 : 1
mixture of imidazole 8b and 6-cyano-2-methylpurine 10b. In
ethanol solution, compound 9b incorporates one equivalent of
ethanol, leading to a white solid isolated in 58% yield and iden-
tified as compound 11 (Scheme 4) by elemental analysis and
1
envisaged. In the H NMR spectrum, the methyl group is a
singlet in the δ 1.8–2.1 ppm region, and the imidazole C–H
shows up in the δ 7.7–8.1 ppm region. From the HMBC spec-
trum, it was possible to identify C(2) in compound 8a (δ 138.0
and 136.9 ppm), C(4) (δ 128.1 and 127.7 ppm) and C(5) (δ 129.1
and 128.6 ppm). The signal for C(4) was also confirmed by the
three-bonds interaction with N–H (δ 11.4 ppm), together with
the signal for the cyano group (δ 115.5 and 113.0 ppm).
The reaction of compound 7a with tosyl isocyanate in
acetonitrile, led to the isolation of the 5-ureidoimidazole 9e
in 68% yield after 10 minutes at Ϫ15 ЊC. The reaction of 7b with
tosyl isocyanate was carried out at 4 ЊC and the imidazole 9b
was isolated in 75% yield after 3 hours. Both compounds 9
show two intense bands in the IR spectrum, which can be
assigned to the carbonyl stretching vibrations, at ν 1723 cmϪ1
(9e) and ν 1711 cmϪ1 (9b) for the urea and at ν 1670 cmϪ1 (9e)
and ν 1686 cmϪ1 (9b) for the acetyl group. The cyano stretching
vibration is a weak absorption at ν 2150 cmϪ1 (9e) and ν 2220
1
cmϪ1 (9b). In the H NMR spectrum, the methyl group of the
acetyl unit is a singlet at δ 2.17 ppm (9e) and δ 2.22 ppm (9b).
The imidazole C–H is also a singlet at δ 7.83 ppm (9e) and
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251
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spectroscopic data. In the IR spectrum it is possible to identify
an intense band at ν 1664 cmϪ1 with a shoulder at ν 1644 cmϪ1
which were assigned to the carbonyl stretching vibrations. The
1H NMR shows a singlet for one proton at δ 7.85 ppm, typical
of the imidazole structure. The HMBC technique indicates that
the signal for the adjacent carbon atom [C(2)] is at δ 135.2 ppm
and the three-bonds interaction enables the identification of
C(4) at δ 130.5 ppm and C(5) at δ 123.1 ppm. The position of
the ethoxy group is clearly indicated in the HMBC spectrum, as
it is possible to identify the three-bonds interaction between the
protons OCH2 (δ 3.4 ppm) and the sp3 carbon atom (δ 78.1
ppm). The NH signal at δ 7.95 ppm interacts with the bands at
δ 123.1 ppm [C(5)] and δ 150.7 ppm (the ureido C᎐O). The NH
᎐
signal at δ 9.06 ppm interacts with the bands at δ 78.1 ppm (the
sp3 carbon atom), δ 115.4 ppm (the CN), δ 130.5 ppm [C(4)] and
δ 169.2 ppm (the acetyl C᎐O).
᎐
When a suspension of compounds 9e or 9b in dry acetonitrile
was stirred at room temperature, the product isolated was the
acetylated 6-amidino-2-oxopurine 12 (12e, 51% yield after
3 hours; 12b, 43% yield after 2 days). When tosyl isocyanate was
added to a suspension of 8a or 8b in acetonitrile, no intermedi-
ates were isolated, and the reaction mixture evolved directly to
the same acetylated 6-amidino-2-oxopurine 12 (12e, 81% yield
after 10 minutes at 0 ЊC; 12b, 66% yield after 1 hour at 4 ЊC).
This unexpected result prompted us to acetylate the 6-amidino-
2-oxopurine 5. When a neat mixture of purines 5e or 5b and
acetic anhydride was stirred at room temperature, compound 12
was again the only product isolated (12e, 88% yield after 8 days;
12b, 84% yield after 3 days).
The position of the acetyl group in compounds 12 was not
easy to identify. These compounds showed a medium–intense
band at ν 1770–1775 cmϪ1 in the IR spectrum, attributed to the
stretching vibration of the carbonyl group in the acetyl unit. In
the 1H NMR spectrum of 12b, the NH signal at δ 8.7 ppm is a
sharp singlet, suggesting a strong intramolecular hydrogen
bonding with N(7). In the HMBC it is possible to see the three-
bond interaction of this proton with C(6) (δ 149.6 ppm).
In compounds 12e and 12b it is also possible to see a four-bond
interaction between the C–H of the methyl group and the
carbon atom of the amidine function (δ 149.7 ppm for 12e and
δ 148.7 ppm for 12b). The 13C NMR spectrum also shows that
the bands assigned to the ring carbon atoms are broad, indicat-
ing that tautomerism is still present. The fact that the acetyl
group must be located on the amidine substituent is further
supported by the reaction of the analogous 6-cyano-2-oxo-
purine 3b with neat acetic anhydride. The starting material
was recovered in 70% yield after 15 days at room temperature,
suggesting that under these conditions, acetylation does not
occur on the ring nitrogen atoms.
Considering that both N-acetylimidazoles 7 and 8 lead to the
same acetylated purine 12 in the presence of tosyl isocyanate,
then the reaction can start either at the 5-amino position or at
the imino nitrogen, leading to the same product through differ-
ent reaction pathways. The observation that the reaction of
imidazoles 8 with tosyl isocyanate is much faster (10 minutes–
1 hour) even at lower temperatures (0–4 ЊC), suggests that the
imino nitrogen must react preferentially when both positions
are free for nucleophilic attack. This indicates that the preferred
pathway for the formation of purine 5 in the reaction of imid-
azole 1 with tosyl isocyanate, must be the one represented in
Scheme 5. This mechanism requires that the intermediate 13,
initially formed, rapidly cyclises onto the adjacent cyano group.
Ring opening of the imidazolone unit in structure 14 generates
a reactive isocyanate function 15, which is promptly trapped by
intramolecular cyclisation with the 5-amino group. The same
type of rearrangement was previously postulated for the reac-
tion of azirines with tosyl isocyanate, where the intermediate
isocyanate was isolated and characterised.9
Scheme 5
and acetic anhydride, indicates that the acetyl group is always
incorporated in the same position of the purine structure,
which must correspond to the thermodynamically stable com-
pound. It is well known that acetyl groups can migrate both
intra- and intermolecularly and this must be responsible for the
facile formation of the thermodynamic product.
Other acyl groups are less prone to migration, which led us to
the use of imidazoles 2 and 16 in the reaction with tosyl iso-
cyanate (Scheme 6). Imidazoles 2 were prepared from the reac-
tion of the appropriate 5-amino-4-cyanoformimidoylimidazole
1 with ethyl chloroformate in dry acetonitrile and pyridine. The
position of the acyl group was confirmed by 1H and 13C NMR
spectroscopy, using the HMBC technique for compound 2a.
Compound 2a was isolated in 50% yield after 1 h at Ϫ15 ЊC,
and compound 2b was isolated in 88% yield after 24 h at 0 ЊC.
Both compounds 2a and 2b were reacted with tosyl isocyanate,
in dry acetonitrile and under a nitrogen atmosphere. Structure
18 could only be isolated in 40% yield from the reaction of 2b,
when the reaction mixture was kept at Ϫ4 ЊC for 15 min and
then at room temperature for 1.5 h. When the reaction mixture
was kept at room temperature for one week, under a dry atmos-
phere, addition of diethyl ether to the homogeneous solution
led to a yellow solid identified as compound 19 (31% yield).
This compound was characterised by elemental analysis and
spectroscopic data. In the IR spectrum, a weak signal at ν 2232
cmϪ1 confirms the presence of the cyano group. Two equally
intense bands are present in the spectrum for each carbonyl
group (ν 1794 and 1767 cmϪ1 possibly for the ester carbonyl and
ν 1699 and 1678 cmϪ1 for the 2-oxo group). This duplication of
bands may indicate the co-existence of conformers E and Z
(19E and 19Z) in the solid state. A similar situation was previ-
ously reported for carbimazole,10 where two carbonyl groups
are present in a comparable relative position. In this case, the
two sets of bands registered in the IR spectrum of this com-
pound were equally assigned to the Z and E conformers. In the
The fact that the same N-acetylpurine 12 is isolated either
from imidazoles 7 or 8 and tosyl isocyanate or from purine 5
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Scheme 6
1H NMR spectrum of compound 19, the singlet at δ 8.97 ppm
with tosyl isocyanate, indicates that when migration of the acyl
was assigned to the C(8)H. In the 13C NMR, the signal for C(8)
was confirmed by DEPT‡ 45 at δ 155.0 ppm. The two carbonyl
carbon atoms were identified at δ 160.9 and 151.1 ppm.
protecting group is difficult, the formation of 6-amidino-2-
oxopurine does not occur. This evidence further supports the
mechanism presented for the reaction of 5-amino-4-cyano-
formimidoylimidazole 1 with tosyl isocyanate, for which the
first step is nucleophilic attack of the imino nitrogen on the
carbon of the isocyanate function.
The difficulties in the isolation of structure 18 are associated
with the ease of hydrolysis of the ureido function, leading
always to the starting material 2b and, in part, to the 6-cyano-2-
oxopurine 3b. All attempts to follow the evolution of this com-
pound by 1H NMR either in deuterated DMSO or acetonitrile
led exclusively to toluene-p-sulfonamide and imidazole 2b.
Compound 17 was isolated in the reaction of imidazole 16
with 2.5 equivalents of tosyl isocyanate, in dry acetonitrile. The
product precipitates out of solution as a pale yellow solid and
was recovered in 51% yield. This compound is very insoluble in
acetonitrile and no evolution is detected when the suspension is
stirred at room temperature for 3 days. In a separate experi-
ment, a catalytic amount of DBU was added to the previous
reaction mixture and the suspension was stirred at room tem-
perature. After 5 days, the starting material was recovered
unchanged. Attempts to characterise compound 17 by NMR
spectroscopy in deuterated DMSO led to complex mixtures. As
soon as this compound is solubilised, a rapid evolution occurs,
and it is possible to identify in the spectrum, the presence of
the 6-cyano-2-oxopurine 3e and the starting material 16. No
evidence is detected for the presence of the 6-amidino-2-
oxopurine. A careful analysis of the 1H and 13C NMR spectra,
using the HMBC technique, enables the unequivocal identifi-
cation of some signals, which can be assigned to structure 17.
The imidazole C–H, at δ 7.70 ppm, shows direct interaction
with the adjacent carbon, at δ 140.0 ppm and three-bonds
interaction with C(4) (δ 127.1 ppm) and C(5) (δ 131.0 ppm).
The assignment of C(5) is further confirmed by the three-bond
interaction with the protons of the CH2 (δ 4.38 ppm). The urea
carbonyl groups show up at δ 150.5 and 160.8 ppm and the
carbamate carbonyl at δ 150.6 ppm.
Experimental
The 5-amino-4-cyanoformimidoylimidazoles 1a2 and 1b–d11
used in this work were prepared by experimental procedures
described previously. Cardice was obtained from Arlíquido,
Portugal.
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.
Analytical data for compounds 2–19 are given in Tables 1–4.
Crystallography§
The crystal was mounted on a glass fibre. All measurements
were made on a CAD4 diffractometer using graphite mono-
chromated Mo-Kα radiation. Data were collected using an
ω/2θ scanning technique up to a maximum 2θ value of 45.0Њ
only, due to the poor diffraction power of the crystal, at room
temperature. The structure was solved by direct methods using
SHELXS-9712 and refined using SHELXL-97.13 The non-
hydrogen atoms were refined anisotropically. The water hydro-
gen atoms could not be located reliably. The other hydrogen
atoms were placed at calculated positions and refined as riding
using the SHELXL-97 defaults.
Crystal data. C20H18N6SO4, C2H4O2, H2O, M = 516.54,
monoclinic, a = 5.063(4) Å, b = 29.246(6) Å, c = 16.325(2) Å,
This study, carried out on the reaction of imidazoles 2 and 16
§ CCDC reference number 157799. See http://www.rsc.org/suppdata/
p1/b0/b010224p/ for crystallographic files in .cif or other electronic
format.
‡ DEPT = distortionless enhancements by polarisation transfer/
techniques.
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Table 1 Analytical data for compounds 2–19
Found (%) (Required)
Compound
(Formula)
Mp/ЊC
(decomp.)
C
H
N
S
m/z (EI)
2a
138–141
(decomp.)
146–160
47.7
(47.8)
57.4
(57.5)
46.8
(46.8)
58.3
(58.4)
47.7
(47.9)
54.6
(54.8)
55.1
(55.4)
56.6
(56.9)
47.9
5.0
(5.2)
5.0
(4.8)
3.4
(3.4)
3.7
(3.4)
4.2
(4.3)
4.1
(4.1)
3.8
(3.5)
4.1
(4.3)
4.0
27.6
(27.9)
22.4
(22.4)
33.8
(34.1)
25.9
(26.2)
22.4
(22.3)
19.2
(19.2)
22.3
(22.6)
19.6
(19.9)
17.2
252 [(M ϩ 1)ϩ, 54%]a
313 (Mϩ, 69%)
(C10H13N5O3)
2b
(C15H15N5O3)
3a
>210
(decomp.)
>280
206 [(M ϩ 1)ϩ, 100%]a
265 (Mϩ, 5%)
(C8H7N5O2)
3b
(C14H11N5O)
5a
>243
(decomp.)
>190
(decomp.)
180–190
(decomp.)
>250
(decomp.)
228–232
377 [(M ϩ 1)ϩ, 100%]a
439 [(M ϩ 1)ϩ, 100%]a
434 [(M ϩ 1)ϩ, 100%]a
423 [(M ϩ 1)ϩ, 100%]a
574 [(M ϩ 1)ϩ, 80%]a
439 [(M ϩ 1)ϩ, 100%]a
(C15H16N6O4S)
5b
7.4
(7.3)
(C20H18N6O4S)
5c
(C20H15N7O3S)
5d
(C20H18N6O3S)
5e
11.5
(11.2)
6.3
(C23H23N7O7S2)
(48.2)
51.2
(51.2)
(4.0)
4.8
(4.7)
(17.1)
16.5
(16.3)
6
303–307
(C20H18N6O3Sؒ
(6.2)
CH3CO2HؒH2O)
7a
>103
(decomp.)
124–125
222.0992c
(221.0991)
222 [(M ϩ 1)ϩ, 100%]a
284 (Mϩ, 100%)b
(C9H11N5O2)
7b
59.6
(59.2)
48.9
(48.9)
59.3
(59.2)
54.2
(54.1)
54.9
4.6
(4.6)
5.0
25.1
(24.7)
31.4
(C14H13N5O2)
8a
>91
222 [(M ϩ 1)ϩ, 100%]a
284 [(M ϩ 1)ϩ, 100%]a
616 [(M ϩ 1)ϩ, 30%]a
481 [(M ϩ 1)ϩ, 40%]a
204 (Mϩ, 100%)b
(C9H11N5O2)
(decomp.)
163–165
(decomp.)
125–132
(5.0)
4.8
(4.6)
4.5
(31.7)
25.0
(24.7)
16.5
8b
(C14H13N5O2)
9a
6.3
(6.3)
6.8
(C25H25N7O8S2)
(4.3)
4.4
(4.2)
4.6
(16.5)
17.7
(17.5)
34.8
9b
>205
(decomp.)
127–128
(C22H20N6O5S)
10a
(55.0)
53.2
(53.2)
(6.7)
(C9H9N5O)
10b
(C14H11N5O)
11
(C24H26N6O6S)
12a
(C25H25N7O8S2)
12b
(C22H20N6O5S)
16
(C15H16N6O2)
17
(C31H30N8O8S)
18
(4.5)
(34.5)
208–210
174–176
266.1045c
266 [(M ϩ 1)ϩ, 100%]a
527 [50%, (M ϩ 1)ϩ]a
616 [(M ϩ 1)ϩ, 30%]a
480.1224c
(266.1042)
54.7
(54.8)
48.5
(48.8)
54.8
5.1
(4.9)
4.3
16.0
(16.0)
15.9
6.2
(6.1)
10.4
(10.4)
6.8
>170
(decomp.)
>210
(decomp.)
167–169
(decomp.)
229–231
(4.1)
4.3
(4.2)
(15.9)
17.3
(17.5)
(55.0)
(6.7)
313.1414c
313 [(M ϩ 1)ϩ, 30%]a
707 [(M ϩ 1)ϩ, 30%]a
511 [(M ϩ 1)ϩ, 100%]a
340 [(M ϩ 1)ϩ, 80%]a
(313.1413)
707.1696c
(707.1706)
141–145
146–153
54.2
(54.1)
56.6
4.5
(4.3)
4.1
16.5
(16.5)
20.4
6.3
(6.3)
(C23H22N6O6S)
19
(C16H13N5O4)
(56.6)
(3.9)
(20.7)
a Fast atom bombardment. b Chemical ionisation. c High resolution mass spectrometry.
U = 2404(2) Å3, β = 95.98(3)Њ, T = 293(2) K, space group P 21/c,
Z = 4, µ(Mo-Kα) = 0.19 cmϪ1, 1863 reflections measured, 1790
unique (Rint = 0.020) which were used in all calculations. The
final wR(F2) was 0.1213 (all data).
solution was obtained. A solid precipitated on cooling and
was filtered and washed with ethanol and diethyl ether. The
product was identified as the purine 5a (0.79 g, 2.10 mmol,
85%).
Synthesis of 9-(2Ј-hydroxyethyl)-2-oxo-N2-tosyl-2,9-dihydro-1H-
purine-6-carboxamidine 5a
Synthesis of 9-(4Ј-methoxyphenyl)-2-oxo-N2-tosyl-2,9-dihydro-
1H-purine-6-carboxamidine 5b
Tosyl isocyanate (1.28 ml, 8.4 mmol) was added with a micro-
syringe to a suspension of imidazole 1a (0.60 g, 3.36 mmol) in
dry acetonitrile (20 ml) kept with efficient stirring under a
nitrogen atmosphere and in an ice–salt bath. An orange solid
formed immediately and the mixture was stirred at 5 ЊC for
19 h. The orange solid had evolved to a yellow solid which
was filtered, washed with acetonitrile and diethyl ether
and identified as the purine 5e (1.93 g, 3.36 mmol, 100%).
When a suspension of 5e (1.42 g, 2.47 mmol) in ethanol
(250 ml) and water (1 ml) was refluxed for 5 h, a homogeneous
Tosyl isocyanate (0.35 ml, 2.3 mmol) was added with a micro-
syringe to a suspension of imidazole 1b (0.50 g, 2.09 mmol) in
dry acetonitrile (10 ml) kept with efficient stirring under a
nitrogen atmosphere and in an ice bath. After the addition, the
mixture was stirred at room temperature, and a yellow solid
started to precipitate out of solution after 30 min. The mixture
was stirred at room temperature for 19 h and the solid was
filtered and washed with acetonitrile and diethyl ether. The
product was identified as the purine 5b (0.86 g, 1.96 mmol,
94%).
1246
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251

View Article Online
Table 2 IR and 1H NMR spectroscopic data for compounds 2–19
Compound
νmax/cmϪ1 (Nujol)
δH (300 MHz; DMSO-d6), J/Hz
2a
3332m, 3225m, 3163m,
3068w, 1665m, 1648m,
1641s
1.25 (3H, t, J 7, CH2CH3), 3.63 (2H, t, J 5, CH2O), 3.95 (2H, t, J 5, CH2N), 4.15 (2H, q, J 7,
CH2CH3), 5.2 (<1H, br s, OH), 7.48 (1H, s, 2-H), 8.20 (2H, s, NH2)
2b
3a
3b
3e
5a
3425m, 3316s, 3113w,
2248m, 1675s, 1626s
3470m, 3391m, 3213s,
3143s, 1612s
1.25 (3H, t, J 7, CH2CH3), 3.82 (3H, s, OCH3), 4.16 (2H, q, J 7, CH2CH3), 7.14 (2H, d, J 9, Ar), 7.46
(2H, d, J 9, Ar), 7.66 (1H, s, 2-H), 8.07 (br s, NH2)
3.80 (2H, t, J 5, CH2O), 4.29 (2H, t, J 5, CH2N), 8.61 (1H, s, 8-H)
3100w, 2050w, 1614s
3.83 (3H, s, OCH3), 7.16 (2H, d, J 8.9, Ar), 7.70 (2H, d, J 8.9, Ar), 8.89 (1H, s, 8-H), 12.6 (1H, br s,
NH)
2.38 (3H, s, CH3), 4.36 (4H, s, OCH2CH2N), 7.36 (2H, d, J 8.7, Ts), 7.68 (2H, d, J 8.7, Ts), 8.50 (1H,
s, 8-H), 12.0 (<1H, br s, NH), 12.6 (<1H, br s, NH)
2.37 (3H, s, CH3), 3.72 (2H, t, J 5, CH2O), 4.17 (2H, t, J 5, CH2N), 5.0 (1H, t, J 5, OH), 7.37 (2H, d,
J 8.7, Ts), 7.84 (2H, d, J 8.7, Ts), 8.41 (1H, s, 8-H), 8.66 (<1H, br s, NH), 9.19 (<1H, br s, NH), 12
(<1H, br s, NH)
3500m, 3105m, 1758s,
1615m
3383m, 3316m, 3204m,
1653s, 1623s
5b
5c
5d
5e
3370s, 3300s, 3240s,
3118m, 1658s, 1643s
2.38 (3H, s, CH3), 3.83 (3H, s, OCH3), 7.15 (2H, d, J 8.9, Ar), 7.39 (2H, d, J 8.7, Ts), 7.69 (2H, d,
J 8.9, Ar), 7.87 (2H, d, J 8.7, Ts), 8.71 (<1H, br s, NH), 8.76 (1H, s, 8-H), 9.2 (<1H, br s, NH), 12.2
(<1H, br s, NH)
2.38 (3H, s, CH3), 7.47 (2H, d, J 8.7, Ts), 7.85 (2H, d, J 8.7, Ts), 8.15 (4H, q, J 8.7, Ar), 8.71 (<1H,
br s, NH), 9.00 (1H, s, 8-H), 9.20 (<1H, br s, NH)
3347m, 3262w, 3115w,
2234w, 1830w, 1708w,
1640s
3365s, 3298w, 3233s,
3126w, 1836w, 1737w,
1658s, 1636s
3390m, 3311m, 3113m,
1747s, 1638s, 1617s,
1600m
2.40 (6H, s, 2 × CH3), 7.39 (4H, d, J 8.7, Ar), 7.68 (2H, d, J 8.7, Ar), 7.91 (2H, d, J 8.7, Ts), 8.71
(<1H, br s, NH), 8.79 (1H, s, 8-H), 9.21 (<1H, br s, NH), 12.20 (<1H, br s, NH)
2.32 (3H, s, CH3), 2.35 (3H, s, CH3), 4.34 (4H, s, NCH2CH2O), 7.33 (2H, d, J 8.7, Ts), 7.36 (2H, d,
J 8.7, Ts), 7.68 (2H, d, J 8.7, Ts), 7.86 (2H, d, J 8.7, Ts), 8.37 (1H, s, 8-H), 8.68 (<1H, br s, NH), 9.16
(<1H, br s, NH), 12 (<2H, br s, 2 × NH)
6
3484m, 3100m, 1709s,
1644s
3287m, 3158m, 3071w,
1647s, 1630s
3402s, 3278s, 3100s,
3100w, 2235w, 1670s,
1629s
2.37 (3H, s, CH3), 3.74 (3H, s, OCH3), 6.93 (2H, d, J 9.0, Ar), 7.39 (2H, d, J 8.7, Ts), 7.82 (2H, d,
J 9.0, Ar), 7.95 (2H, d, J 8.7, Ts), 8.26 (1H, s, 7-H), 10.00 (<1H, br s, NH), 10.11 (<1H, vbr s, NH)
2.22 (3H, s, CH3), 3.63 (2H, q, J 5, CH2O), 3.95 (2H, t, J 5, CH2N), 4.34 (<1H, br s, OH), 7.48 (1H,
s, 2-H)
2.23 (3H, s, CH3), 3.82 (3H, s, OCH3), 7.44 (2H, d, J 8.7, Ar), 7.66 (2H, d, J 8.7, Ar), 7.66 (1H, s,
2-H), 8.19 (2H, br s, NH2)
7a
7b
8a
8b
3532m, 3431m, 3197s,
3121s, 3058m, 2240w,
1696s, 1624m, 1601s
A: 2.04 (3H, s, CH3), 3.60 (2H, q, J 5, CH2O), 3.79 (2H, t, J 5, CH2N), 7.83 (1H, s, 2-H), 10.11
(<1H, br s, NH), 11.37 (1H, s, NH)
B: 2.10 (3H, s, CH3), 3.60 (2H, q, J 5, CH2O), 3.79 (2H, t, J 5, CH2N), 4.34 (<1H, br s, OH), 7.77
(1H, s, 2-H), 9.84 (<1H, br s, NH), 12.40 (1H, s, NH)
A: 1.97 (3H, s, CH3), 3.80 (3H, s, OCH3), 7.11 (2H, d, J 8.7, Ar), 7.35 (2H, d, J 8.7, Ar), 8.11 (1H, s,
2-H), 11.06 (<1H, br s, NH), 12.6 (<1H, br s, NH)
B: 1.86 (3H, s, CH3), 3.80 (3H, s, OCH3), 7.11 (2H, d, J 8.7, Ar), 7.35 (2H, d, J 8.7, Ar), 8.02 (1H, s,
2-H), 10.63 (<1H, br s, NH)
3420m, 3219s, 3173m,
3102m, 2238w, 1682s,
1650w, 1602s
9b
9e
11
3223m, 2220w, 1711s,
1686s, 1642m, 1604s
2.22 (3H, s, COCH3), 2.39 (3H, s, CH3), 3.80 (3H, s, OCH3), 6.94 (2H, d, J 8.7, Ar), 7.20 (2H, d,
J 8.7, Ar), 7.35 (2H, d, J 8.1, Ts), 7.67 (2H, d, J 8.1, Ts), 8.11 (1H, s, 2-H), 8.82 (1H, br s, NH),
11.6 (<1H, br s, NH)
2.17 (3H, s, COCH3), 2.37 (3H, s, CH3), 2.39 (3H, s, CH3), 4.37 (2H, t, J 5, CH2O), 4.50 (2H, t, J 5,
CH2N), 7.37 (2H, d, J 8.3, Ts), 7.42 (2H, d, J 8.3, Ts), 7.77 (4H, d, J 8.3, 2 × Ts), 7.83 (1H, s, 2-H),
8.82 (1H, br s, NH), 12 (<2H, br s, 2 × NH)
0.96 (3H, t, J 7, CH2CH3), 1.90 (3H, s, COCH3), 2.40 (3H, s, CH3), 3.40 (2H, q, J 7, CH2CH3),
3.78 (3H, s, OCH3), 6.84 (2H, d, J 9.0, Ar), 7.15 (2H, d, J 9.0, Ar), 7.36 (2H, d, J 8.1, Ts), 7.68 (2H,
d, J 8.1, Ts), 7.85 (1H, s, 2-H), 7.95 (1H, s, NH), 9.06 (1H, s, NH), 11.2 (<1H, br s, NH)
2.88 (3H, s, CH3), 3.89 (2H, q, J 5, CH2O), 4.39 (2H, t, J 5, CH2N), 5.1 (1H, t, J 5, OH), 8.89 (1H, s,
8-H)
2.74 (3H, s, CH3), 3.84 (3H, s, OCH3), 7.18 (2H, d, J 8.7, Ar), 7.73 (2H, d, J 8.7, Ar), 9.11 (1H, s,
8-H)
3606s, 3394s, 3152m,
3093m, 2150w, 1754s,
1723s, 1670s
3303s, 3205m, 2066w,
1664s, 1644m
10a
10b
10e
12b
3273s, 3103m, 2250w
3106w, 2245w
2256w, 1738s
2.39 (3H, s, CH3), 2.72 (3H, s, CH3), 4.39 (2H, t, J 5, CH2O), 4.49 (2H, t, J 5, CH2N), 7.34 (2H, d,
J 8.7, Ts), 7.65 (2H, d, J 8.7, Ar), 8.73 (1H, s, 8-H)
2.36 (3H, s, COCH3), 2.39 (3H, s, CH3), 3.85 (3H, s, OCH3), 7.19 (2H, d, J 8.9, Ar), 7.39 (2H, d,
J 8.0, Ts), 7.70 (2H, d, J 8.9, Ar), 7.87 (2H, d, J 8.0, Ts), 8.74 (1H, br s, NH), 9.09 (1H, s, 8-H), 9.23
(1H, br s, NH)
3366m, 3300m, 3147m,
1770s, 1635s
12e
3378m, 3236m, 3304m,
1775m, 1624s
2.36 (3H, s, CH3), 2.38 (3H, s, COCH3), 2.39 (3H, s, CH3), 4.38 (2H, t, J 5, CH2O), 4.47 (2H, t, J 5,
CH2N), 7.35 (2H, d, J 8.7, Ts), 7.47 (2H, d, J 8.7, Ts), 7.70 (2H, d, J 8.7, Ts), 7.87 (2H, d, J 8.7, Ts),
8.70 (<1H, br s, NH), 8.72 (1H, s, 8-H), 9.21 (<1H, br s, NH), 12.1 (<1H, br s, NH)
3.64 (2H, br s, CH2O), 3.94 (2H, t, J 5, CH2N), 4.35 (2H, d, J 6, CH2Ph), 5.07 (<1H, br s, OH),
7.27–7.33 (5H, m, Ph), 7.34 (1H, s, H2), 7.77 (1H, br s, NH), 8.35 (1H, t, J 6, NH)
2.31 (3H, s, CH3), 2.36 (3H, s, CH3), 4.38 (4H, s, NCH2CH2O), 4.41 (2H, d, J 6, CH2Ph), 7.2–7.4
(9H, m, 2 × Ts, Ph), 7.6–7.8 (5H, m, 2 × Ts, H-2), 8.35 (1H, t, J 6, NH), 8.69 (1H, br s, NH), 12.1
(2H, br s, 2 × NH)
1.29 (3H, br s, CH3), 2.40 (3H, s, CH3), 3.80 (3H, s, OCH3), 4.30 (2H, br s, CH2), 6.93 (2H, br s, Ar),
7.24 (2H, br s, Ar), 7.20 (2H, d, J 8.7, Ar), 7.35 (2H, d, J 8.1, Ts), 7.67 (2H, d, J 8.1, Ts), 8.11 (1H, s,
2-H), 8.60 (<1H, s, NH), 8.75 (<1H, s, NH), 11.4 (<1H, br s, NH), 11.6 (<1H, br s, NH)
1.37 (3H, t, J 7, CH3), 3.82 (3H, s, OCH3), 4.54 (2H, q, J 7, CH2), 7.14 (2H, d, J 9, Ar), 7.63 (2H, d,
J 9, Ar), 8.97 (1H, s, 8-H)
16
17
3322s, 2240s, 2240w,
1630s
3380m, 3333m, 3180m,
3100w, 2256w, 1750m,
1721s, 1679s, 1639m
3269m, 3208m, 3142w,
2236w, 1719s, 1615m
18
19
3127w, 2232w, 1794s,
1767s, 1699s, 1678s,
1656m
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251
1247

Table 3 δC (75 MHz, DMSO-d6) for imidazoles 2, 7, 8, 9, 16 and 17
Compound
2-C
4-C
5-C
6-C
CN
R1
R2
R3
2a
2b
7a
7b
8a
139.0
138.2
139.8
139.0
A: 138.0
B: 136.9
A: 138.0
B: 137.7
139.1
139.4
136.4
121.4
120.9
151.2
150.8
151.5
154.5
A: 129.1
B: 128.6
A: 129.9
B: 127.7
130.1
132.0
149.0
137.5
138.0
111.9
111.7
45.8, 58.7
55.6, 115.1, 125.3, 127.2, 159.8
—
—
—
—
—
12.3, 61.6, 161.2
14.2, 61.7, 160.9
122.5
132.5
112.5
46.5, 59.6
25.5, 184.1
a
a
a
a
a
A: 128.1
B: 127.7
A: 128.8
B: 127.3
129.3
127.3
119.5
A: 145.1
B: 142.9
A: 144.7
B: 142.7
131 (br)
130 (br)
A: 115.5
B: 113.0
A: 112.8
B: 112.1
46.4, 59.5
22.7, 171.0 (A), 170.1 (B)
22.4, 170.3
8b
55.5, 114.8, 126.3, 126.5, 159.5
—
9b
9e
16
17
18
114.6
55.6, 114.6, 126.2, 126.4, 159.6
21.1, 42.7, 63.6, 127.5, 129.8, 136.0, 144.5, 150.7
45.5, 58.9
21.1, 42.2, 63.3, 127.5, 129.7, 136.1, 144.5, 150.6
55.5, 114.5, 126.2, 126.3, 159.6
21.1, 127.3, 129.4, 136.7, 143.8, 150.5
21.1, 127.4, 129.5, 136.7, 144.0, 150.5
—
21.1, 127.4, 129.5, 136.8, 144.3, 150.5
21.1, 127.1, 129.3, 136.7, 143.8, 149.7
24.5, 182.2
24.4, 182.2
43.5, 128.4, 127.4, 126.9, 139.6, 160.7
43.4, 127.1, 127.3, 128.5, 138.8, 160.8
14.0, 63.5, 160 (br)
b
136.4
112.5
110.5
110
b
140
138.5
127.1
129.3
131
131.8
135 (br)
a In DMSO solution, compound 7b evolves rapidly to compound 8b, and most of the signals are not visible. b Peaks not visible in the spectrum.
Table 4 δC (75 MHz, DMSO-d6) for purines 3, 5, 10 and 12
Compound
2-C
4-C
5-C
6-C
8-C
R1
R2
R3
3a
3b
161.7
161.8
160.2
160.8
160.6
160.7
160.2
161.7
163.9
161.9
157.9
157.7
156.1
155.4
156.5
155.8
155.5
155.8
156.5
154.8
153.2
153.7
154.9
155.4
129.0
129.7
125.8
126.2
130.0
130.0
125.8
129.3
131.2
128.3
130.4
130.0
131.6
131.0
146.6
146.8 (br)
148.3
147.8
146 (br)
134.0
133.2
132.6
149.1
147.7
147.5
146.0
145.0
145.5
147.3
150.6
146.6
150.6
154.6
154.2
46.1, 58.8
55.6, 114.7, 125.6, 126.4, 159.1
45.7, 58.7
—
—
—
—
—
—
—
25.4
25.9
25.3
—
114.3
114.1
5a
21.0, 129.3, 126.3, 139.3, 142.6, 158.8
21.0, 129.4, 126.4, 139.4, 142.7, 158.0
20.9, 126.3, 128.3, 139.1, 142.7, 157.9
20.9, 142.6, 129.3, 126.3, 139.1, 157.9
21.0, 127.4, 129.4, 139.2, 142.8, 157.7
114.5
5b
55.6, 114.7, 125.4, 126.4, 159.4
118.2, 127.5, 129.5, 131.0, 137.6
20.9, 123.3, 127.8, 131.0, 137.6
21.1, 41.8, 63.3, 127.7, 129.6, 136.1, 144.3, 150.5
46.3, 58.8
55.7, 115.3, 125.3, 126.2, 159.1
21.1, 42.4, 63.6, 128.5, 129.5, 136.1, 144.2, 150.5
55.6, 114.9, 125.6, 126.3, 159.3
21.0, 42.5, 63.3, 129.6, 127.3, 136.2, 144.3, 150.4
5c
5d
5e
10a
10ba
10e
12b
12e
113.7
114.4
149.6
148.7
20.6, 21.0, 129.4, 126.3, 139.2, 142.7, 148.7, 168.6
20.6, 21.0, 126.4, 129.4, 139.8, 142.3, 149.7, 168.6
—
a CDCl3.

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Synthesis of 9-(4Ј-cyanophenyl)-2-oxo-N2-tosyl-2,9-dihydro-1H-
purine-6-carboxamidine 5c
Synthesis of 5-acetamido-4-(C-cyanoformimidoyl)-1-
(2Ј-hydroxyethyl)-1H-imidazole 8a
A suspension of imidazole 1c (0.12 g, 0.51 mmol) in dry
acetonitrile (15 ml) was kept at 0 ЊC under a nitrogen atmos-
phere with magnetic stirring. A solution of tosyl isocyanate (0.2
g, 1.02 mmol) in dry acetonitrile (ca. 1 ml) was added dropwise
through the serum cap over a period of 15 min. An orange
suspension was formed and this evolved to a homogeneous
orange solution while still in the ice bath. Immediately after the
removal of the ice bath, a pale yellow solid started to precipitate
out of solution, and the mixture was stirred at room temper-
ature for 18 hours, when the solid was filtered and washed with
diethyl ether to give compound 5c (0.22 g, 0.51 mmol, 99%).
A suspension of 7a (0.48 g, 2.2 mmol) in ethanol (50 ml) was
stirred at room temperature. A homogeneous solution was
obtained after 25 min and 10 min later, it was indicated by TLC
that all the starting material had been consumed. The ethanol
was partially removed in the rotary evaporator and the solid
precipitated out on cooling. Ethyl acetate was added and the
solid was filtered and washed with ethyl acetate and diethyl
ether to give compound 8a (0.39 g, 1.8 mmol, 82%).
Synthesis of 5-acetamido-4-(C-cyanoformimidoyl)-1-
(4Ј-methoxyphenyl)-1H-imidazole 8b
A suspension of imidazole 7b (0.42 g, 1.47 mmol) in ethanol
(50 ml) was stirred at 4 ЊC for 7 h. n-Hexane was added to the
homogeneous solution, which was concentrated in the rotary
evaporator until a white solid precipitate was formed. The solid
was filtered and washed with cold diethyl ether. The product
was identified as compound 8b (0.39 g, 1.17 mmol, 80%).
Synthesis of 2-oxo-9-(4Ј-tolyl)-N2-tosyl-2,9-dihydro-1H-purine-
6-carboxamidine 5d
A suspension of imidazole 1c (0.43 g, 1.91 mmol) in dry
acetonitrile (15 ml) was kept at 0 ЊC under a nitrogen atmos-
phere with magnetic stirring. A solution of tosyl isocyanate
(0.76 g, 3.78 mmol) in dry acetonitrile (ca. 2.5 ml) was added
dropwise through the serum cap over a period of 30 min. The
resulting orange suspension was stirred at room temperature
for 4 h, when the starting material was no longer present (as
evidenced by TLC). The yellow solid was filtered and washed
with diethyl ether to give compound 5d (0.77 g, 1.82 mmol,
96%).
Reaction of 4-[N-acetyl-C-(cyanoformimidoyl)]-5-amino-1-
(2Ј-hydroxyethyl)-1H-imidazole 7a with tosyl isocyanate
A suspension of imidazole 7a (0.5 g, 2.26 mmol) in dry
acetonitrile (20 ml) was kept stirring at Ϫ15 ЊC (slush of
Cardice and ethylene glycol) under a nitrogen atmosphere.
Tosyl isocyanate (0.90 ml, 5.94 mmol) was added with a
microsyringe through the serum cap and the mixture was stirred
at Ϫ15 ЊC for 10 min. The white solid was filtered rapidly,
washed with acetonitrile and identified as compound 9e (0.95 g,
1.55 mmol, 68%). The mother liquor was kept stirring at room
temperature, under a nitrogen atmosphere, and after one week
the white solid was filtered and washed with acetonitrile and
diethyl ether. The product was identified as compound 12e
(0.34 g, 0.55 mmol, 24%).
Synthesis of 4-(4Ј-methoxyphenyl)amino-8-(N-tosylimino)-
7,8-dihydropyrimido[5,4-d]pyrimidin-2(1H)-one 6b
Method A. Acetic acid (4 ml) and water (0.5 ml) were added
to a solution of purine 5b (0.16 g, 0.37 mmol) in DMF (6 ml).
The mixture was refluxed for 15 h, when almost no starting
material was detected on TLC. Addition of water to the cold
reaction mixture led to a yellow solid which was filtered and
washed with cold water, acetonitrile and diethyl ether. The
product was identified as compound 6b (0.06 g, 0.14 mmol,
38%).
Reaction of 4-[N-acetyl-C-(cyanoformimidoyl)]-5-amino-1-
(4Ј-methoxyphenyl)-1H-imidazole 7b with tosyl isocyanate
A suspension of imidazole 7b (0.51 g, 1.78 mmol) in dry
acetonitrile (10 ml) was kept in an ice bath under a nitrogen
atmosphere. Tosyl isocyanate (0.33 ml, 2.15 mmol) was added
with a microsyringe through the serum cap and the mixture was
stirred at 4 ЊC for 3 h. The deep yellow solid was filtered and
washed with acetonitrile and diethyl ether. The product was
identified as compound 9b (0.64 g, 1.33 mmol, 75%).
Method B. Ammonium acetate (0.12 g, 1.56 mmol) was
added to a suspension of purine 5b (0.21 g, 0.48 mmol) in
glacial acetic acid (10 ml). A brownish-yellow solution was
obtained after refluxing the mixture for 4 h. A yellow solid
precipitated on cooling and was filtered and washed with water
and then with a large volume of diethyl ether. The greenish-
yellow solid was identified as compound 6b (0.18 g, 0.41 mmol,
86%). δC(75 MHz; DMSO-d6; Me4Si) 21.1 (Me), 55.3 (OMe),
113.6 (Cm, Ar), 123.9 (Co, Ar), 127.2 (br, Co, Ts), 129.5 (Cm, Ts),
130.8 (Ci, Ar), 138.0 (Ci, Ts), 143.5 (Cp, Ts), 145.1 (6-C), 154.0
(4-C), 156.3 (Cp, Ar), 157.6 (2-C).
Reaction of 4-[N-acetyl-C-(cyanoformimidoyl)]-5-(3Ј-tosyl-
ureido)-1-(4Ј-methoxyphenyl)-1H-imidazole 9b with ethanol
A solution of imidazole 9b (0.06 g, 0.11 mmol) in ethanol (1 ml)
was stirred at room temperature for 2 days. The white solid was
filtered, washed with acetonitrile and diethyl ether and identi-
fied as compound 11 (0.04 g, 0.66 mmol, 58%). δC(75 MHz;
DMSO-d6; Me4Si) 14.4 (CH2CH3), 21.1 (Ts), 22.7 (COCH3),
55.4 (OCH3), 60.6 (CH2CH3), 78.1, 114.3 (Cm, Ar), 115.4 (CN),
123.1 (4-C), 126.1 (Co, Ar), 127.1 (Ci, Ar), 127.2 (Co, Ts), 129.4
(Cm, Ts), 130.5 (5-C), 135.2 (2-C), 136.8 (Ci, Ts), 143.8 (Cp, Ts),
150.7 (CONHTs), 159.0 (Cp, Ar), 169.2 (CO CH3).
Synthesis of 4-[N-acetyl-C-(cyanoformimidoyl)]-5-amino-1-
(2Ј-hydroxyethyl)-1H-imidazole 7a
Acetic anhydride (0.8 ml, 0.86 g, 8.5 mmol) was added to a
suspension of 1a (0.72 g, 4.0 mmol) in acetonitrile (8 ml) and
the mixture was stirred at 0–4 ЊC. The reaction was complete
after 19 h, as the off-white solid became deep yellow. Chloro-
form (25 ml) and a few drops of diethyl ether were added to the
suspension, which was filtered and washed with chloroform and
diethyl ether to give compound 7a (0.70 g, 3.2 mmol, 79%).
Synthesis of 2-oxo-9-(2Ј-tosylaminocarbonyloxyethyl)-N1-
acetyl-N2-tosyl-2,9-dihydro-1H-purine-6-carboxamidine 12e
From 5e. A suspension of purine 5e (0.20 g, 0.35 mmol) in
acetic anhydride (2 ml) was stirred at room temperature for
8 days. The white solid was filtered and washed with acetonitrile
and diethyl ether. The product was identified as 12e (0.19 g, 0.31
mmol, 88%).
Synthesis of 4-[N-acetyl-C-(cyanoformimidoyl)]-5-amino-1-
(4Ј-methoxyphenyl)-1H-imidazole 7b
A suspension of imidazole 1b (0.33 g, 1.38 mmol) in acetic
anhydride (1.0 ml) was stirred at 4 ЊC for 24 h, when the TLC
showed the absence of the starting material. The yellow solid
was filtered and washed with cold diethyl ether. The product
was identified as compound 7b (0.27 g, 0.97 mmol, 70%).
From 8a. Tosyl isocyanate (0.33 ml, 2.20 mmol) was added
to a suspension of imidazole 8a (0.22 g, 1.00 mmol) in dry
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251
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acetonitrile (20 ml) kept stirring in an ice–salt bath under a
nitrogen atmosphere. A white solid immediately precipitated
from the reaction mixture, which was stirred at 0 ЊC for a
further 10 min. The solid was filtered and washed with
acetonitrile and diethyl ether, but the solid was completely dry
only after 2 weeks in the desiccator. The white solid was
identified as the purine 12e (0.05 g, 0.81 mmol, 81%).
and was filtered and washed with chloroform. The product was
identified as imidazole 2a (0.20 g). A second crop of this com-
pound was obtained from dry flash chromatography using
acetone as eluant (0.12 g). The total isolated yield of imidazole
2a was (0.32 g, 1.25 mmol, 50%).
Synthesis of 5-amino-4-[N-(ethoxycarbonyl)-C-(cyanoform-
imidoyl)]-1-(4Ј-methoxyphenyl)-1H-imidazole 2b
From 9e. Method A. A suspension of 9e (0.26 g, 0.42 mmol)
in acetonitrile (10 ml) was stirred at room temperature for 3 h.
The white solid was filtered and washed with acetonitrile and
diethyl ether. The product was identified as compound 12e
(0.13 g, 0.21 mmol, 51%). The mother liquor was stirred at
room temperature for 2 days, leading to a white solid which was
identified as compound 10e (0.04 g, 0.10 mmol, 24%).
Method B. A suspension of 9e (0.50 g, 2.26 mmol) in dry
acetonitrile (20 ml) was stirred at room temperature and under
a nitrogen atmosphere. After 1 day, the white solid was filtered
and washed with acetonitrile and diethyl ether. The product was
identified as compound 12e (0.34 g, 1.54 mmol, 67%).
Dry pyridine (0.61 ml, 0.60 g, 7.59 mmol) was added to a sus-
pension of imidazole 1b (1.21 g, 5.0 mmol) in acetonitrile (30
ml), kept stirring in an ice bath and under a nitrogen atmos-
phere. Addition of ethyl chloroformate (0.58 ml, 0.66 g,
6.1 mmol) led to a homogeneous solution and 10 min later a
yellow solid started to be formed. The mixture was stirred at
5 ЊC for 19 h, when the solid was filtered and washed with
chloroform. The product was identified as compound 2b
(1.37 g, 4.39 mmol, 88%).
Synthesis of 6-cyano-9-(4Ј-methoxyphenyl)-9H-purin-2-(1H)-one
3b
Synthesis of 2-oxo-9-(4Ј-methoxyphenyl)-N1-acetyl-N2-tosyl-
2,9-dihydro-1H-purine-6-carboxamidine 12b
A suspension of compound 2b (0.61 g, 1.95 mmol) in
acetonitrile (50 ml) was taken to the ultra-sound bath for
2–3 min, and then was stirred at room temperature. Addition
of DBU (0.30 ml, 1.95 mmol), led to a homogeneous solution,
which was stirred at room temperature for 3 days. Acetic acid
(0.15 ml, 2.63 mmol) was added, and 2 h later the solvent was
partially removed in the rotary evaporator. The mixture was
stirred at room temperature for 19 h, and the white solid that
precipitated out of the solution was filtered and washed with
ethyl acetate and diethyl ether (0.18 g). Two more crops of the
same compound were obtained from the mother liquor (0.14 g)
and were combined to give a total yield for compound 3b of
(0.32 g, 1.20 mmol, 62%).
From 5b. A suspension of purine 5b (0.21 g, 0.47 mmol) in
acetic anhydride (2 ml) was stirred at room temperature for
3 days. The white solid was filtered and washed with diethyl
ether. The product was identified as 12b (0.19 g, 0.40 mmol,
84%).
From 8b. Tosyl isocyanate (0.11 ml, 0.14 g, 0.73 mmol) was
added to a suspension of imidazole 8b (0.17 g, 0.59 mmol) in
dry acetonitrile (10 ml) kept stirring in an ice bath under a
nitrogen atmosphere. A deep yellow colour developed immedi-
ately and the mixture was stirred at 4 ЊC for 1 h. The white solid
suspension was filtered and washed with acetonitrile and
diethyl ether. The product was identified as the purine 12b
(0.19 g, 0.39 mmol, 66%).
Reaction of 5-amino-4-[N-(ethoxycarbonyl)-C-(cyanoform-
imidoyl)]-1-(2Ј-hydroxyethyl)-1H-imidazole 2a with tosyl
isocyanate
A suspension of imidazole 2a (0.21 g, 0.82 mmol) in dry
acetonitrile (3 ml) was kept stirring in an ice–salt bath under a
nitrogen atmosphere. Tosyl isocyanate (0.36 ml, 0.47 g, 2.38
mmol) was added, leading to an orange solution. After 4 h,
TLC indicated that the starting material had been consumed,
leading to at least four different compounds. The mixture was
stirred at room temperature for 20 h, when a second crop of
tosyl isocyanate (0.1 ml, 0.13 g, 0.67 mmol) was added. After
2 days at room temperature, the yellow solid suspension was
filtered and washed with acetonitrile and diethyl ether. The pale
yellow solid was identified as the 6-cyano-2-oxopurine 3e (0.02
g, 0.05 mmol, 6%). Dry flash chromatography on the mother
liquor led to the isolation of toluene-p-sulfonamide (0.17 g),
using diethyl ether as eluant. The second crop, isolated with the
same eluant, was a white solid identified as ethyl N-tosyl-
carbamate (0.13 g, 0.57 mmol, 69%). The use of ethyl acetate
led to a yellow solid which was a mixture of at least four
components (by TLC) and was abandoned.
From 9b. A solution of 9b (0.13 g, 0.44 mmol) in dry
acetonitrile (10 ml) was kept stirring at room temperature and
under a nitrogen atmosphere for 2 days. The white solid was
filtered and washed with acetonitrile and diethyl ether. The
product was identified as compound 12b (0.05 g, 0.10 mmol,
40%). An off-white solid was isolated from the mother liquor,
and was identified as compound 10b (0.05 g, 0.19 mmol, 43%).
Synthesis of 9-(4Ј-methoxyphenyl)-2-methyl-9H-purine-6-
carbonitrile 10b
DBU (2 µl) was added to a suspension of imidazole 7b (0.05 g,
0.18 mmol) in acetonitrile (1.5 ml) and the mixture was stirred
at room temperature. A dark solution was obtained, from
which a white solid precipitated. After 3 h, the solid was filtered
and washed with acetonitrile and diethyl ether. The product was
identified as compound 10b (0.03 g, 0.13 mmol, 71%).
Synthesis of 5-amino-4-[N-(ethoxycarbonyl)-C-(cyanoform-
imidoyl)]-1-(2Ј-hydroxyethyl)-1H-imidazole 2a
Reaction of 5-amino-4-[N-(ethoxycarbonyl)-C-(cyanoform-
imidoyl)]-1-(4Ј-methoxyphenyl)-1H-imidazole 2b with tosyl
isocyanate
A suspension of imidazole 1a (0.45 g, 2.5 mmol) in dry
acetonitrile (30 ml) was kept at Ϫ15 ЊC under a nitrogen atmos-
phere with magnetic stirring. Dry pyridine (0.3 ml, 3.7 mmol)
was added through the serum cap followed by ethyl chloro-
formate (0.28 g, 2.6 mmol), which was added dropwise over a
period of 30 min. As the temperature was allowed to rise slowly
to room temperature a dark brown suspension developed in a
clear yellow solution. The suspension was removed by filtration
through glass-fibre paper and the solution was concentrated to
a small volume in the rotary evaporator. Chloroform (30 ml)
was added and a yellow solid precipitated after 19 h at Ϫ10 ЊC
Method A. A suspension of imidazole 2b (0.39 g, 1.25 mmol)
in dry acetonitrile (4 ml) was kept stirring in an ice–salt bath
under a nitrogen atmosphere. Tosyl isocyanate (0.38 ml, 0.50 g,
2.51 mmol) was added with a microsyringe through the serum
cap and the mixture was stirred in the ice bath. After 40 min a
homogeneous yellow solution was obtained, leading to a yellow
solid suspension 35 min later. The mixture was stirred for a
further 1.5 h when the solid was filtered and washed with
acetonitrile and diethyl ether (0.06 g). A second crop of the
1250
J. Chem. Soc., Perkin Trans. 1, 2001, 1241–1251

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same compound was isolated from the mother liquor (0.20 g).
The two crops were combined as they corresponded to the same
product, identified as compound 18 (0.26 g, 0.51 mmol, 40%).
The starting material 2b (0.08 g, 0.27 mmol, 21%) was also
recovered from the mother liquor.
was stirred at room temperature for 30 min and then at 5 ЊC for
19 h, when the reaction was complete as evidenced by TLC.
The pale yellow solid was filtered, washed with acetonitrile and
diethyl ether, and identified as compound 17 (0.64 g, 0.91
mmol, 51%).
Method B. A suspension of imidazole 2b (0.21 g, 0.68 mmol)
in dry acetonitrile (10 ml) was kept stirring in an ice–salt bath
under a nitrogen atmosphere. Tosyl isocyanate (0.16 ml, 0.20 g,
1.02 mmol) was added with a microsyringe through the serum
cap and the mixture was stirred in the ice bath for 10 min and
then at room temperature. A homogeneous yellow solution was
obtained and stirring was continued for one week. Addition of
diethyl ether led to a yellow solid which was filtered and washed
with diethyl ether. The product was identified as compound 19
(0.07 g, 0.21 mmol, 31%). δC(75 MHz; DMSO-d6; Me4Si) 13.5
(CH2CH3), 55.6 (OCH3), 60.9 (CH2CH3), 109.1 (5-C), 114.7
(Cm, Ar), 114.5 (CN), 125.2 (Co, Ar), 125.7 (Ci, Ar), 130.5 (6-C),
150.6 (4-C), 151.1 (COOEt), 155.0 (8-C), 159.1 (Cp, Ar), 160.9
(2-C). Dry flash chromatography on the mother liquor led to
the isolation of the starting material 2b (0.07 g, 0.23 mmol,
33%) when ethyl acetate was used as the eluant. The diethyl
ether fraction gave a yellow solid (0.02 g) which proved to be a
complex mixture by 1H NMR, where it is possible to identify a
small amount of the 2-oxo-6-cyanopurine 3b.
Acknowledgements
Thanks are due to the PRAXIS XXI program (PRAXIS/C/
QUI/10101/98) and to the University of Minho and the
Foundation for Science and Technology, Portugal, for financial
support.
References
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Synthesis of 5-amino-4-[N-(benzylcarbamoyl)-C-(cyanoform-
imidoyl)]-1-(2Ј-hydroxyethyl)-1H-imidazole 16
A suspension of imidazole 1a (0.51 g, 2.82 mmol) in dry
acetonitrile (5 ml) was stirred in an ice–salt bath, under a nitro-
gen atmosphere. Benzyl isocyanate (0.7 ml, 0.75 g, 5.64 mmol)
was added with a microsyringe through the serum cap. The
mixture was kept at 0 ЊC for 3 days, during which time the
suspension gradually developed an orange colour. The solid
was filtered and washed with acetonitrile and diethyl ether, to
give compound 16 as an orange solid (0.83 g, 2.67 mmol, 95%).
7 M. Hocek, M. Masojídková and A. Holy, Collect. Czech. Chem.
Commun., 1997, 62, 136.
8 M. J. Alves, B. L. Booth, M. A. Carvalho, A. M. Dias and M. F.
Proença, J. Chem. Res. (S), 1996, 212; M. J. Alves, B. L. Booth,
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M. F. Proença and A. S. Ramos, J. Chem. Res. (S), 1993, 402; M. J.
Alves, B. L. Booth, O. K. Al-Duaij, P. Eastwood, L. Nezhat, M. F.
Proença and A. S. Ramos, J. Chem. Res. (M), 1993, 2701.
12 G. M. Sheldrick, SHELXS-97, Program for the solution of crystal
structures, University of Göttingen, Germany, 1997.
13 G. M. Sheldrick, SHELXL-97, Program for the refinement of
crystal structures, University of Göttingen, Germany, 1997.
14 G. K. Johnson, ORTEP II, Report ORNL-5138, Oak-Ridge
National Laboratory, Tennessee, USA, 1976.
Reaction of 5-amino-4-[N-(benzylcarbamoyl)-C-(cyanoform-
imidoyl)]-1-(2Ј-hydroxyethyl)-1H-imidazole 16 with tosyl
isocyanate
A suspension of imidazole 16 (0.56 g, 1.79 mmol) in dry
acetonitrile (3 ml) was stirred in an ice bath, under a nitrogen
atmosphere. Tosyl isocyanate (0.70 ml, 0.91 g, 4.62 mmol) was
added with a microsyringe through the serum cap. The mixture
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