The synthesis of 6-amidino-2-oxopurine revisited: New evidence for the reaction mechanism

Article abstract of DOI:10.1002/ejoc.200601025

Treatment of N-aryl- or N-alkyl-5-amino-4-(cyanoformimidoyl)-1H-imidazoles 1 with benzoyl or ethoxycarbonyl isocyanates resulted in the formation of 5-amino-4-[N-benzoyl-or N-(ethoxycarbonyl)carbamoylcyanoformimidoyl]-1H- imidazoles 2. In the presence of

Full text of DOI:10.1002/ejoc.200601025

FULL PAPER
DOI: 10.1002/ejoc.200601025
The Synthesis of 6-Amidino-2-oxopurine Revisited: New Evidence for the
Reaction Mechanism
Alice M. Dias,[a] Isabel Cabral,[a] A. Sofia Vila-Chã,[a] Daniela S. Costa,[a] and
M. Fernanda Proença*[a]
Keywords: Nitrogen heterocycles / Amidinopurines / Isocyanates / Rearrangement / 4,4Ј-Biimidazoles
Treatment of N-aryl- or N-alkyl-5-amino-4-(cyanoformimi-
doyl)-1H-imidazoles 1 with benzoyl or ethoxycarbonyl iso-
cyanates resulted in the formation of 5-amino-4-[N-benzoyl-
mation of purines 5 both from imidazoles 2 and from bi-imid-
azoles 3 was followed by H NMR, allowing a deeper under-
standing of the reaction mechanism. The rearrangements are
acid-catalysed (trifluoroacetic acid), but the use of one equiv-
alent of acid produced different products, identified as the
bi-imidazoles 8.
1
or
N-(ethoxycarbonyl)carbamoylcyanoformimidoyl]-1H-
imidazoles 2. In the presence of catalytic amounts of DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene), these compounds cy-
clized to give the 5Ј-amino-5-imino-4,4Ј-bi-1H-imidazol-
2(5H)-ones 3. Compounds 3 efficiently rearrange to yield 6-
amidino-2-oxopurines 5 in ethanol or DMF solution. The for-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
iodoimidazoles[7] or from an N-protected 4-substituted
imidazole and an appropriate spacer incorporated between
the two heterocyclic units, in two to five steps.[8] The pre-
pared 4,4Ј-biimidazole derivatives have been used as bridg-
ing ligands for two-dimensional transition metal complex-
es[7b] or as building blocks for supramolecular assemblie-
s.[8a,8b,9] Their use as molecular probes for peripheral sites
of the zinc endopeptidase of botulinum neurotoxin sero-
type A, a potential bioterror agent for which there is no
chemical antidote, has also been reported.[8c]
Introduction
Purine-based compounds display an impressively wide
range of biological activities and find potential for applica-
tion mainly as therapeutic agents.[1] The potencies and
selectivities of these compounds are intimately related to
the position and nature of the substituents on the rings. The
synthesis of new purine derivatives and the development of
new versatile synthetic methods that will allow the prepara-
tion of diverse libraries of these compounds is a highly im-
portant topic.[2]
Recent work in our group on reactions between tosyl iso-
cyanate and N-aryl- or N-alkyl-5-amino-4-(cyanoformimi-
doyl)-1H-imidazoles 1 showed that this is a mild and ef-
ficient method for the synthesis of 6-amidino-2-oxopurines
5 (R1 = alkyl or aryl, R2 = tosyl).[10] The synthetic pathway
postulated for this reaction (Scheme 1) regarded intermedi-
ates 2 and 3 as plausible precursors of purines 5, the only
compounds isolated under the experimental conditions
used (acetonitrile at 0 to –15 °C). In subsequent studies,
imidazoles 1 (R1 = alkyl or aryl) were treated with alkyl,
aryl and allyl isocyanates and in this case it was possible to
isolate and characterize the ureas 2.[11] Addition of DBU to
suspensions of compounds 2 in acetonitrile proved to be an
efficient synthetic method leading to 4,4Ј-bi-imidazolones
3. The formation of purines 5 requires ring-opening of the
imidazolone units in compounds 3, giving rise to reactive
isocyanate functions (4), the precursors of 2-oxopurines 5.
Attempts to generate purines 5 from bi-imidazoles 3 (R2 =
alkyl, aryl or allyl) failed in all these cases.[11]
The biological importance of puromycin and of a
number of N-substituted or N,N-disubstituted derivatives
is documented in previous publications.[3] From structure/
activity relationship studies, it has been established that, in
some cases, a basic group in the 6-position is essential for
activity.[4] Unlike in the cases of adenine and adenine deriv-
atives, which have been extensively studied, only a few re-
ports on the synthesis of purines possessing a strongly basic
carboxamidino substituent at the 6-position are available.
The formation of these compounds has been claimed to oc-
cur through nucleophilic attack by a primary or secondary
amine on a 6-cyanopurine,[5] or through addition of ammo-
nium chloride to an imidate intermediate, generated by
treatment of a 6-cyanopurine with catalytic amounts of so-
dium methoxide in methanol.[6]
A limited number of publications on the synthesis of
4,4Ј-biimidazoles are available. These compounds have been
prepared by palladium-catalysed coupling of N-protected 4-
The results suggest that this type of rearrangement can
only occur when R2 is an electron-withdrawing group. In
order to understand the circumstances that enable the for-
[a] Departamento de Química, Universidade do Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
E-mail: fproenca@quimica.uminho.pt
Eur. J. Org. Chem. 2007, 1925–1934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1925

A. M. Dias, I. Cabral, A. S. Vila-Chã, D. S. Costa, M. F. Proença
FULL PAPER
Scheme 1.
mation of a 6-amidino-2-oxopurine 5 or the isolation of a der nitrogen at low temperature (0 to –15 °C) in the pres-
stable 4,4Ј-bi-1H-imidazol-2(5H)-one 3, acyl isocyanates ence of excess isocyanate (1.4 to 2.5 molar equivalents) and
were treated with N-alkyl- and N-aryl-5-amino-4-(cyano- in acetonitrile as solvent. Under these experimental condi-
formimidoyl)imidazoles 1.
tions, fast reactions occur (20 min to 7 h) and ureas 2 pre-
cipitate from the reaction mixtures as yellow-orange solids,
isolated in very good yields. The reaction between imidazole
1c (R1 = Me) and tosyl isocyanate was also carried out at
–4 °C, giving a poor isolated yield of 2f (12%). In this case
the major product (79%) was purine 5f, rapidly formed in
Results and Discussion
The reactions between imidazoles 1 and benzoyl or
ethoxycarbonyl isocyanates (Scheme 2) were carried out un-
1926
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1925–1934

6-Amidino-2-oxopurine Synthesis
FULL PAPER
the reaction mixture by further reaction of 2f. A reduction dicarbonyl unit, occurring to a different extent for each
of the temperature to –15 °C and stirring of the reaction compound and each solvent system used for recrystalli-
mixture for 10 min resulted in the isolation of an orange zation. The tautomeric equilibrium is clearly affecting the
solid identified as 2f (39%) from its elemental analysis and imidazole carbon atoms in compound 2d, as all the signals
IR spectrum. As soon as the solid is dissolved in [D6]- in the 13C NMR spectrum are broad ([D6]DMSO solution).
1
1
DMSO, the H NMR spectrum indicates that imidazole 2f In the H NMR spectra, the chemical shifts for the urea
and bi-imidazolone 3f are present as an equilibrium mixture N–H groups in imidazoles 2a–f (δ = 10.35–11.60 ppm) and
in approximately 1:1 ratio. Purine 5f is also identified in the for the imine N–H moieties in 4,4Ј-biimidazoles 3a–f (δ =
spectrum, as a result of the further reaction of 3f. The sec- 10.40–10.75 ppm) are high, as would be expected for an
ond crop is again purine 5f (52%).
acidic proton. Table 1 shows the chemical shifts for these
protons ([D6]DMSO solution) and also includes previously
reported data for analogous compounds.[10,11]
The figures indicate that the substituent R1 (alkyl or aryl)
in the 1-position of the imidazole ring does not substan-
tially affect the chemical shift of the N–H proton. This
value gradually increases as R2 changes, though, in the or-
der Et, Bu Ͻ allyl Ͻ CH2Ph Ͻ Ph Ͻ 4-CF3C6H5 Ͻ COOEt
Ͻ COPh. The Hammett constants (σI and σR) for these
substituents were calculated[12] in order to study the rela-
tionship between these values and the experimentally mea-
sured N–H chemical shifts. The Hammett plot for the δN–
H systems in compounds 2 exhibited poor correlation both
with σR (R2 = 0.757) and with σI (R2 = 0.855). Slightly
better results were registered in the Hammett plots for the
N–H chemical shifts of compounds 3 and σR (R2 = 0.890)
or σI (R2 = 0.815). We can envisage a slight predominance
of the inductive effect of the substituent R2 over the reso-
nance effect in compounds 2 and the opposite situation in
compounds 3. Nevertheless, the possibility of tautomeric
equilibria and especially of intramolecular hydrogen bond-
ing may be affecting the acidities of the N–H protons and
the corresponding chemical shift values.
Scheme 2.
Compounds 2 usually show a very weak band in the IR
spectrum in the 2222–2234 cm–1 region, assigned to the
stretching vibration of the cyano group. This band was ab-
sent, however, in the IR spectrum of imidazole 2e, but the
Addition of base (0.02 to 0.25 molar equivalents of
presence of the cyano group was confirmed by 13C NMR, DBU) to suspensions of imidazoles 2 in acetonitrile results
as a weak band at δ = 112.7 ppm. For the other imidazoles in the formation of stable anions, followed by rapid intra-
2, the cyano group was identified in the same spectral re- molecular cyclization to give 4,4Ј-bi-1H-imidazol-2(5H)-
gion (δ = 112.0–112.7 ppm). The carbonyl stretching vi- ones 3, which precipitate from the reaction mixtures. The
bration in the IR spectrum occurred over a range from 1759 reactions occur at room temperature or in an ice bath. Tri-
to 1712 cm–1, which may be due to tautomerism in the β- ethylamine (1 molar equivalent) was also used for the cycli-
1
Table 1. H NMR chemical shifts for the acidic N–H systems of compounds 2 and 3 in [D6]DMSO solutions.
R1
R2
δ N–H for compounds 2
δ N–H for compounds 3
σR
σI
[a]
(CH2)2OCONHEt
4-CH3OC6H4
4-CH3OC6H4
CH2CH2OH
4-CH3OC6H4
4-CH3OC6H4
CH2CH2OH
CH2CH2OH
4-CH3OC6H4
CH2CH2OH
4-CH3OC6H4
CH2CH2OH
4-CH3OC6H4
Et
Et
nBu
allyl
7.88
7.99
7.98
8.01
8.17
8.35
8.35
10.00
10.18
10.27
10.43
10.35 (2b)
10.50 (2a)
10.80 (2d)
10.80 (2e)
10.90 (2c)
11.60 (2f)
–0.14
–0.14
–0.15
–0.14
–0.14
–0.13
–0.13
–0.11
–0.11
0.01
0.01
0.11
0.11
0.11
–0.01
–0.01
–0.01
0.02
0.02
0.00
0.00
0.12
0.12
0.19
0.19
0.30
0.30
0.31
0.31
0.31
0.54
9.60
9.76
9.73
9.78
9.80
9.77
allyl
CH2Ph
CH2Ph
Ph
10.06
10.08
10.21
10.23
10.75 (3b)
10.80 (3a)
Ph
4-CF3C6H4
4-CF3C6H4
COOEt
COOEt
[b]
(CH2)2OCONHCOPh COPh
Me
4-CH3OC6H4
Me
(3d)
COPh
COPh
Ts
10.44 (3e)
10.40 (3c)
10.60 (3f)[c]
0.11
0.11
0.11
[a] Not prepared. [b] Not isolated. [c] Detected in the reaction mixture.
Eur. J. Org. Chem. 2007, 1925–1934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1927

A. M. Dias, I. Cabral, A. S. Vila-Chã, D. S. Costa, M. F. Proença
FULL PAPER
zation of 2e (R1 = CH3, R2 = COPh) and the reaction was
equally fast at room temperature, providing the product 3e
in 90% isolated yield.
The cyclization of compound 2f (R1 = CH3, R2 = Ts) is
exceptionally fast, even in the absence of base. It occurs
spontaneously in the reaction mixture, the only stable com-
pound being purine 5f, which can be isolated in a good
yield.
The further reactions of compounds 3a and 3e to give
the corresponding purines 5 were carried out at room tem-
perature in ethanol or DMF. The reactions took 3–12 d,
mainly due to the insolubility of the bi-imidazoles 3 in these
solvents. Faster and more efficient reactions occurred when
solutions of imidazoles 2 in large volumes of DMF or etha-
nol were stirred at room temperature, as the bi-imidazoles
3 were kept in solution. The IR spectra of bi-imidazoles 3
indicate that the cyano groups are no longer present, whilst
two intense bands in the 1750–1740 cm–1 and 1710–
1670 cm–1 regions can be assigned to the carbonyl stretch-
ing vibrations. All compounds give poor 13C NMR spectra
due to their low solubilities in [D6]DMSO.
The 6-amidinopurines 5a, 5c and 5g were treated with
hydrazine hydrate in either ethanol or acetonitrile as sol-
vents (Scheme 2). Reactions occurred at room temperature,
the amidine functions all being transformed into amidra-
zone substituents, to afford purine 6, isolated as yellow so-
lid in excellent yields. This result supports the structure as-
signed to the parent compound 5.
Figure 1. a) 1H NMR study of the reaction behaviour of imidazole
2a (ᮀ) in [D6]DMSO solution (4 mg in 700 µL) at 20 °C. Other
compounds detected in solution: bi-imidazole 3a (✧) and purine
5a (᭺). b) 1H NMR study of the reaction behaviour of bi-imidazole
3a (✧) in [D6]DMSO solution (4 mg in 700 µL) at 20 °C. Other
compounds detected in solution: imidazole 2a (ᮀ) and purine 5a
(᭺).
A similar situation was identified when the reaction be-
1
In order to understand the mechanism for purine forma- haviour of 2e or 3e was followed by H NMR (Figure 2).
tion both from the ureas 2 and from the bi-imidazoles 3, In both cases an equilibrium mixture was rapidly formed,
the reaction behaviour of these compounds was followed by in which only compounds 2e, 3e and 5e could be identified.
1H NMR in [D6]DMSO solution.
The concentration of approximately 50% of purine 5e had
been reached after 70 min (from 2e) or 40 min (from 3e), at
20 °C.
1H NMR studies carried out on the reaction behaviour
of 2b and 3b indicated that the two compounds follow a
NMR Study of the Evolution of Imidazoles 2
and 3
1
similar pattern (Figure 3). When the H NMR spectrum of
a solution of 2 mg of 3b in [D6]DMSO (600 µL) was mea-
1
A H NMR study on the formation of purines 5 from sured at regular intervals, four different compounds were
either 2 or 3 was carried out, the reactions being monitored identified as the only products after 10 min at 20 °C. Com-
by measurement of the disappearance of the proton signals pounds 2b, 3b and 5b had been isolated and characterized
of the imidazole rings in compounds 2 (δ = 7.61 for 2a, δ previously, allowing a clear identification of their presence
= 7.49 for 2b, δ = 7.55 ppm for 2e) and 3 (δ = 7.85 for 3a, in solution.
δ = 7.64 for 3b, δ = 7.67 ppm for 3e) and the appearance of
From the set of peaks corresponding to the fourth com-
the proton signals of the heterocycles 5 (δ = 8.71 for 5a, δ pound, it was possible to identify an imidazole C–H (δ =
= 8.41 for 5b, δ = 8.44 ppm for 5e). Compound 8 was moni- 7.54 ppm), one N–H group (δ = 10.45 ppm) and a broad
tored by the signal at δ = 7.59 ppm, attributed to the imid- signal at δ = 9.7 ppm integrating for two protons and as-
azole proton.
signed to an NH2 group. This compound could never be
The formation of purine 5a from either 2a or 3a (Fig- isolated or characterized by other methods and was tenta-
ure 1) indicates that the reaction is fast. When bi-imidazole tively identified as having structure 7 (Scheme 3).
3a was used as the starting material, the concentration of
The concentrations of compound 7 and of 2b decreases
purine 5a had reached 50% after 10–15 min at 20 °C. When in a similar way with time, suggesting that they both exist
the reaction was carried out from imidazole 2a, the same in equilibrium with 3b. The formation of purine 5b from
concentration of purine was registered after 15–20 min. In 3b continuously displaces this equilibrium, resulting in the
both cases, a rapid equilibrium between 3a and 2a is estab- purine being the only product in solution after less than
lished in solution, resulting in similar molar ratios of these one day. The addition of a catalytic amount of trifluoro-
compounds (2.1–2.5), with 3a always present as the major acetic acid (TFA) to the reaction mixture (2 mg of 3b in
component.
600 µL of [D6]DMSO) does not affect the reaction mecha-
1928
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1925–1934

6-Amidino-2-oxopurine Synthesis
FULL PAPER
Figure 2. a) 1H NMR study of the reaction behaviour of imidazole
2e (ᮀ) in [D6]DMSO solution (2 mg in 600 µL) at 20 °C. Other
compounds detected in solution: bi-imidazole 3e (✧) and purine 5e
(᭺). b) 1H NMR study of the reaction behaviour of bi-imidazole
3e (✧) in [D6]DMSO solution (2 mg in 600 µL) at 20 °C. Other
compounds detected in solution: imidazole 2e (ᮀ) and purine 5e
(᭺).
Figure 3. a) 1H NMR study of the reaction behaviour of imidazole
2b (ᮀ) in [D6]DMSO solution (4 mg in 700 µL) at 20 °C. Other
compounds detected in solution: bi-imidazole 3b (✧), purine 5b
(᭺) and an intermediate compound with the assigned structure 7
(∆). b) 1H NMR study of the reaction behaviour of bi-imidazole
3b (✧) in [D6]DMSO solution (2 mg in 600 µL) at 20 °C. Other
compounds detected in solution: imidazole 2b (ᮀ), purine 5b (᭺)
and an intermediate compound with the assigned structure 7 (∆).
nism but does slightly enhance the rate of reaction (Fig-
ure 4, a). The concentration of purine 5b has reached 50%
after ca. 4 h at 20 °C in the absence of acid, and after ca.
3 h with acid catalysis.
The reaction behaviour of 3b in the presence of one
equivalent of TFA was also followed by 1H NMR (Figure 4,
b). Compound 3b was consumed rapidly, and only a trace
amount was present in solution after one hour at room tem-
perature. Structure 3b both reverted back to imidazole 2b
three carbonyl groups, with stretching vibrations at 1781,
1745 and 1698 cm–1. This observation is confirmed by 13C
NMR, with signals at δ = 161.0, 159.5 and 148.4 ppm.
General Mechanistic Discussion
The considerable amounts of compounds 2 detected
(ca. 15%) and transformed into the purine 5b (ca. 20%) when compounds 3 are dissolved in [D6]DMSO (see parts
and into a new compound identified as 8 (ca. 65%), with b in Figures 1, 2 and 3) indicate that the imidazolone rings
simultaneous elimination of ammonia (the ammonium salt can open across two different C–N bonds. Either the imid-
was identified in the spectrum as a triplet at δ = 7.10 ppm, azoles 2 are regenerated or an isocyanate function is formed
J = 51 Hz). After 3 d at 18 °C, a very small amount of imid- and ultimately cyclizes with the 5-amino group to afford
azole 2b was detectable in the spectrum. Compounds 8 and purines 5 (Scheme 3). The irreversible formation of purines
5b were present in a 5.5:2 ratio, together with minor prod- 5 continuously displaces this equilibrium, and no other
ucts probably arising from degradation processes.
products were detected in solution when the reactions were
Compound 8 was prepared in a separate experiment, carried out from 2a, 2e, 3a or 3e. The further reaction to
when a suspension of 3b in DMSO, was combined with one afford 6-amidino-2-oxopurines 5 only occurs when the sub-
equivalent of trifluoroacetic acid and the mixture was stituent R2 on the bi-imidazole 3 incorporates a carbonyl
stirred at room temperature for 5 hours and kept for 2 d at or a sulfonyl group. When compound 3 (R2 = 4-CF3C6H4)
–18 °C. An orange solid was isolated and identified as 8 (2 mg) was dissolved in [D6]DMSO (600 µL) with a cata-
(66%) from its elemental analysis and spectroscopic data. lytic amount of trifluoroacetic acid, no transformations had
The signal for the acidic N–H system is no longer present occurred after 8 d at 20 °C. This result indicates that the
1
in the H NMR spectrum but the NH2 group appears as a substituent R2 plays an important role in the ring-opening
singlet at δ = 8.56 ppm. The chemical shift of the heterocy- process that affords purine 5. A possible explanation for the
clic C–H (δ = 7.59 ppm) clearly indicates that it is part of an ring-opening of compounds 3a–f might be that, in this case,
imidazole structure. The IR spectrum shows the presence of two stable hydrogen bonds can be established, one of them
Eur. J. Org. Chem. 2007, 1925–1934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1929

A. M. Dias, I. Cabral, A. S. Vila-Chã, D. S. Costa, M. F. Proença
FULL PAPER
Scheme 3.
between the acidic N–H and the imidazole nitrogen (3A)
and the other between the same N–H and the oxygen of
the double bond (3B) (Scheme 3).
From 3A no further reaction occurs, and ring-opening
may reverse the equilibrium back to imidazole 2, as the
zwitterion 2A, in equilibrium with the neutral compound
2B. From 3B, ring-opening may proceed to give the inter-
mediate isocyanates 4, the common precursors of bi-imid-
azoles 7 (pathway b) and purines 5 (pathway a). Bi-imid-
azoles 7 are the result of intramolecular cyclization involv-
ing the amino and the isocyanate groups. Purines 5 are
formed when intramolecular cyclization involves the imino
and isocyanate groups. Dynamic equilibria between com-
pounds 4 and 7 may ultimately result in the formation of
purines 5 as the only products.
Ring-opening of 3b to generate the intermediate 4 is ac-
celerated by acid catalysis (trifluoroacetic acid). The ad-
dition of one equivalent of acid to a solution of compound
3b (2 mg) in [D6]DMSO (600 µL) resulted in a mixture of
imidazoles 2b and 3b, which completely reacted to give bi-
imidazole 8 through hydrolysis of the exocyclic imine bond.
Conclusions
The reactions between 5-amino-4-(cyanoformimidoyl)-
imidazole and isocyanates after addition of DBU can be
considered an efficient synthetic method for 4,4Ј-biimid-
azolyl-2-ones except when tosyl or acyl isocyanates are
used. In those cases the biimidazole-2-ones spontaneously
react further, in solution, to give 6-carboxamidinopurines,
which are also isolated in excellent yields. The mechanism
for this reaction does not depend on the substituent on the
Figure 4. a) 1H NMR study of the reaction behaviour of bi-imid-
azole 3b (✧) in [D6]DMSO solution (2 mg in 600 µL) at 20 °C, in
the presence of TFA catalysis. Other compounds detected in solu-
tion: imidazole 2b (ᮀ), 7 (∆) and purine 5b (᭺). b) 1H NMR study
of the reaction behaviour of bi-imidazole 3b (✧) in [D6]DMSO
solution (2 mg in 600 µL) at 20 °C, in the presence of 1 equivalent
of TFA. Other compounds detected in solution: imidazole 2b (ᮀ),
purine 5b (᭺) and 8 (∆).
1930
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1925–1934

6-Amidino-2-oxopurine Synthesis
FULL PAPER
C11H14N6O4.H2O (312.29) calcd. C 42.31, H 5.16, N 26.917; found
C 42.45, H 5.33, N 26.87.
imidazole nitrogen, as alkyl and aryl imidazoles follow a
similar pathway (Scheme 1). The reaction is slow when
compounds 2b or 3b are used as starting materials and their
5-Amino-4-[(N-benzoylcarbamoyl)cyanoformimidoyl]-1-(4-methoxy-
phenyl)-1H-imidazole (2c): Yield 1.51 mmol, 91%; m.p. 207 °C
1
reaction behaviour, followed by H NMR in a [D6]DMSO
1
(dec.). H NMR ([D6]DMSO, 300 MHz): δ = 10.90 (s, 1 H), 8.69
solution, shows the formation of a fourth compound (to-
gether with structures 2, 3 and 5) tentatively identified as
7. This compound was not detected when the study was
performed with compounds 2a, 3a, 2e and 3e. These reac-
tions are much faster and the only products detectable by
1H NMR are compounds 2, 3 and 5. Addition of a catalytic
amount of trifluoroacetic acid catalyses the formation of
the purine ring from the bi-imidazoles 3, but the use of one
equivalent of acid results in the formation of a different
product identified as 8. The N-tosyl and N-acyl amidine
functions in the 6-positions of purines 5 proved to be excel-
lent precursors of the amidrazone substituent by nucleo-
philic substitution with hydrazine.
(s, 2 H), 7.84 (d, J = 7.5 Hz, 2 H), 7.67 (s, 1 H), 7.60 (t, J = 7.5 Hz,
1 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.47 (d, J = 9.0 Hz, 2 H), 7.14 (d,
J = 9.0 Hz, 2 H), 3.83 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 166.7, 159.8, 157.8, 151.7, 139.2, 136.4, 134.4, 132.2,
128.4, 128.2, 127.4, 125.4, 123.2, 115.2, 112.5, 55.6 ppm. IR (Nujol
mull): ν = 3557, 3450, 3085, 2222 (CN), 1748, 1712, 1691, 1674,
˜
1643 cm–1. C20H16N6O3 (388.39) calcd. C 61.85, H 4.15, N 21.64;
found C 61.72, H 4.19, N 21.45.
5-Amino-4-[(N-benzoylcarbamoyl)cyanoformimidoyl]-1-[2-(benzoyl-
carbamoyloxy)ethyl]-1H-imidazole (2d): Yield 3.13 mmol, 95 %;
1
m.p. 150 °C (dec.). H NMR ([D6]DMSO, 300 MHz): δ = 11.02 (s,
1 H), 10.80 (s, 1 H), 9.00 (s, 2 H), 7.85 (d, J = 7.5 Hz, 2 H), 7.83
(d, J = 7.5 Hz, 2 H), 7.66 (s, 1 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.60
(m, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.49 (d, J = 7.5 Hz, 2 H), 4.40
(t, J = 5.0 Hz, 2 H), 4.25 (t, J = 5.0 Hz, 2 H) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 170.4, 167.6, 158.0, 151.0, 141 (br.) 136.7
(br.), 133.9, 133.7, 132.8, 129.6, 129.5, 129.3, 129.0, 128.2, 124.6,
Experimental Section
63.8, 43.0 ppm. IR (Nujol mull): ν = 3310, 3350, 3170, 2219 (CN),
˜
General Remarks: The (Z)-N1-(2-amino-1,2-dicyanovinyl)-N2-aryl-
and -N2-methylformamidines and the 5-amino-1-aryl-4-(cyano-
formimidoyl)imidazoles used in this work were prepared by pre-
viously described procedures.[13] NMR spectra were recorded on a
Varian Unity Plus instrument (1H: 300 MHz, 13C: 75 MHz), in-
1770, 1720, 1660, 1640 cm–1. C23H19N7O5·H2O (491.46) calcd. C
56.21, H 4.31, N 19.95; found C 56.50, H 4.24, N 19.50.
Reaction between 5-Amino-4-(cyanoformimidoyl)-1-methylimidazole
(1c) and Benzoyl Isocyanate. Formation of 2e and 5e: A suspension
of imidazole 1c (0.40 g, 2.69 mmol) in dry acetonitrile (25 mL) was
stirred under nitrogen at –15 °C for 5 min. Addition of benzoyl
isocyanate (0.59 g, 4.03 mmol) produced an orange suspension. Af-
ter stirring for 30 min at –15 °C, the orange solid was filtered under
nitrogen and washed with acetonitrile and diethyl ether. The solid
was identified as 2e; 0.55 g, 1.85 mmol, 70%); m.p. 225 °C (dec.).
1H NMR ([D6]DMSO, 300 MHz): δ = 10.80 (s, 1 H), 8.86 (s, 2 H),
7.85 (d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.55 (s, 1 H),
7.51 (t, J = 7.5 Hz, 2 H), 3.47 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 166.6, 157.9, 152.6, 140.2, 134.4, 132.2, 128.4, 128.2,
1
cluding the H–13C correlation spectra (HMQC and HMBC), and
deuterated DMSO was used as solvent. IR spectra were recorded
on a Bomem MB 104 FT-IR instrument with use of Nujol mulls
and NaCl cells. The reactions were monitored by thin-layer
chromatography (TLC) on silica gel 60 F254 (Merck). The melting
points were determined on a Gallenkamp melting point apparatus
and are uncorrected. Elemental analyses were performed on a
LECO CHNS-932 instrument.
General Procedure for the Preparation of 4-[(N-Acylcarbamoyl)-
cyanoformimidoyl]-5-amino-1H-imidazoles (2): A suspension of 1 in
dry acetonitrile (8–12 mL) was stirred under N2 at 0 to –15 °C for
5–10 min. After 10 min the isocyanate (1.4–2.5 molar equivalents)
was added to the mixture, which was stirred at low temperature
until no starting material was detectable by TLC. The yellow/
orange suspension was filtered and washed with acetonitrile and
diethyl ether to give compounds 2a–d.
124.4, 112.7, 30.2 ppm. IR (Nujol mull): ν = 3609, 3583, 3300,
˜
3160, 1712, 1657, 1638 cm–1. C14H12N6O2·1/4H2O (300.79) calcd.
C 55.90, H 4.19, N 27.94; found C 56.13, H 4.31, N 27.97.
The mother liquor was stirred at –15 °C for a further 2 h, resulting
in a yellow solid, which was filtered and washed with acetonitrile
and diethyl ether. The solid was identified as 5e (0.03 g, 0.10 mmol,
4%); m.p. 265 °C (dec.). 1H NMR ([D6]DMSO, 300 MHz): δ =
11.80 (br. s, 1 H), 10.10 (br. s, 1 H), 9.15 (br. s, 1 H), 8.44 (s, 1 H),
8.32 (d, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.48 (t, J =
7.5 Hz, 2 H), 3.65 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz):
δ = 178.4, 160.0, 158.8, 157.9, 149.2, 144 (br.), 136.7, 132.3, 129.6,
5-Amino-4-[(N-ethoxycarbonylcarbamoyl)cyanoformimidoyl]-1-(4-
methoxyphenyl)-1H-imidazole (2a): Yield 2.97 mmol, 100 %; m.p.
1
175–178 °C. H NMR ([D6]DMSO, 300 MHz): δ = 10.50 (s, 1 H),
8.45 (s, 2 H), 7.61 (s, 1 H), 7.45 (d, J = 9.0 Hz, 2 H), 7.14 (d, J =
9.0 Hz, 2 H), 4.10 (q, J = 7.0 Hz, 2 H), 3.83 (s, 3 H), 1.21 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 159.9,
157.3, 151.9, 151.4, 138.6, 136.6, 127.5, 125.4, 122.5, 115.5, 112.5,
128.1, 124.3, 29.3 ppm. IR (Nujol mull): ν = 3350, 3240, 3127,
˜
3060, 1720, 1637 cm–1. Elemental analysis (%) for C14H12N6O2
(296.29) calcd. C 56.75, H 4.08, N 28.36; found C 56.91, H 4.22,
N 28.12.
60.7, 55.6, 14.3 ppm. IR (Nujol mull): ν = 3390, 3313, 3200, 2232
˜
(CN), 1759, 1675, 1631 cm–1. C16H16N6O4 (356.34) calcd. C 53.93,
H 4.53, N 23.58; found C 54.02, H 4.78, N 23.89.
Reaction between 5-Amino-4-(cyanoformimidoyl)-1-methylimidazole
(1c) and Tosyl Isocyanate Formation of 2f and 5f. Method A: A solu-
tion of imidazole 1c (0.40 g, 2.69 mmol) in dry acetonitrile (35 mL)
was stirred under nitrogen in an ice/salt bath (–4 °C). After 3 min,
5-Amino-4-[(N-ethoxycarbonylcarbamoyl)cyanoformimidoyl]-1-(2-
hydroxyethyl)-1H-imidazole (2b): Yield 2.05 mmol, 73%; m.p. 142–
1
144 °C. H NMR ([D6]DMSO, 300 MHz): δ = 10.35 (s, 1 H), 8.65 tosyl isocyanate (1.07 g, 5.45 mmol) was added, producing an
(s, 2 H), 7.49 (s, 1 H), 5.07 (s, 1 H), 4.11 (q, J = 7.0 Hz, 2 H), 3.96
orange suspension. After 10 min at –4 °C, the solid was filtered off
(t, J = 5.0 Hz, 2 H), 3.64 (t, J = 5.0 Hz, 2 H), 1.23 (t, J = 7.0 Hz, and washed with acetonitrile and diethyl ether. The product was
2 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 157.4, 152.01,
identified as 2f (0.11 g, 0.32 mmol, 12%); m.p. 260 °C (dec.). 1H
NMR ([D6]DMSO, 300 MHz): δ = 11.60 (br. s, 1 H), 8.52 (br. s, 2
H), 7.81 (d, J = 8.0 Hz, 2 H), 7.51 (s, 1 H), 7.42 (d, J = 8.0 Hz, 2 H),
151.98, 139.7, 135.8, 123.5, 112.0, 60.6, 58.6, 45.6, 14.3 ppm. IR
(Nujol mull): ν = 3376, 3293, 3152, 2230 (CN), 1755, 1650 cm–1.
˜
Eur. J. Org. Chem. 2007, 1925–1934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1931

A. M. Dias, I. Cabral, A. S. Vila-Chã, D. S. Costa, M. F. Proença
5Ј-Amino-1-benzoyl-5-imino-1Ј-(4-methoxyphenyl)-4,4Ј-bi-1H-imid-
FULL PAPER
3.44 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ
= 157.9, 152.6, 140.6, 129.5, 127.4, 30.2, 21.1 ppm (the remaining
signals are not visible in the spectrum due to the rapid further
transformation into 3f and 5f). C14H14N6O3S·1.25H2O (368.88)
calcd. C 45.58, H 4.51, N 22.78, S 8.93; found C 45.58, H 4.47, N
23.08, S 8.74. The following signals in the NMR spectra were as-
signed to compound 3f: 1H NMR ([D6]DMSO, 300 MHz): δ =
10.60 (s, 1 H), 8.12 (s, 2 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.67 (s, 1
H), 7.42 (d, J = 8.0 Hz, 2 H), 3.44 (s, 3 H), 2.38 (s, 3 H) ppm. 13C
NMR ([D6]DMSO, 75 MHz): δ = 159.7, 156.2, 154.1, 152.7, 145.2,
141.7, 135.7, 129.8, 127.5, 114.7, 30.3, 20.9 ppm. IR (Nujol mull):
1
azol-2(5H)-one (3c): Yield 0.32 mmol, 82%; m.p. 252 °C (dec.). H
NMR ([D6]DMSO, 300 MHz): δ = 10.40 (s, 1 H), 7.96 (s, 2 H),
7.86 (s, 1 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.67 (m, 1 H), 7.50 (t, J =
8.0 Hz, 2 H), 7.49 (d, J = 9.0 Hz, 2 H), 7.16 (d, J = 9.0 Hz, 2 H),
3.83 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 168.0,
160.2, 159.9, 159.9, 140.1, 133.7, 130.0, 128.8, 128.4, 127.4, 125.4,
115.2, 55.6 ppm (note: three peaks are not visible). IR (Nujol mull):
ν = 3363, 3263, 3250, 1737, 1686, 1642, 1603 cm–1. MS (FAB) m/z
˜
(rel. int.) 367 [M + 1]+, 93. HRMS (FAB) m/z for C20H16N6O3
calcd. 389.1362; found 389.1352.
ν = 3584, 3556, 2255, 1668, 1648, 1587 cm–1. The mother liquor
˜
Cyclization of 2d with DBU. Method A: A solution of DBU (0.02 g,
0.14 mmol) in acetonitrile (25 mL) was added to imidazole 2d
(0.27 g, 0.57 mmol). The orange suspension was stirred at room
temperature for 15 min, producing an orange solid, which was fil-
tered off and washed with acetonitrile and diethyl ether. The solid
was identified as the starting material 2d (0.12 g, 0.25 mmol, 43%).
The mother liquor was concentrated in the rotary evaporator to
provide a yellow solid that was filtered and washed with acetonitrile
and diethyl ether. The product was identified as the 6-amidinopu-
rine 5d (0.07 g, 0.15 mmol 26 %); m.p. 219 °C (dec.). 1H NMR
([D6]DMSO, 300 MHz): δ = 11.4–11.2 (br. s, 1 H), 11.00 (s, 1 H),
10.2 (br. s, 1 H), 9.15 (br. s, 1 H), 8.59 (s, 1 H), 8.32 (d, J = 8.0 Hz,
2 H), 7.82 (d, J = 7.5 Hz, 2 H), 7.6–7.5 (m, 2 H), 7.5–7.4 (m, 4 H),
4.51 (t, J = 5.0 Hz, 2 H), 4.44 (t, J = 5.0 Hz, 2 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 178.5, 166.0, 158.8, 158.5, 158.0, 151.2,
148.9, 143.6, 136.7, 133.3, 132.6, 132.3, 129.6, 128.4, 128.3, 128.2,
was stirred at room temperature for 45 min. The yellow suspension
was filtered off and washed with acetonitrile and diethyl ether. The
product was identified as 5f (0.74 g, 2.14 mmol, 79%); m.p. 290 °C
(dec.). 1H NMR ([D6]DMSO, 300 MHz): δ = 12.10 (br. s, 1 H),
9.17 (br. s, 1 H), 8.67 (br. s, 1 H), 8.42 (s, 1 H), 7.84 (d, J = 8.0 Hz,
2 H), 7.36 (d, J = 8.0 Hz, 2 H), 3.69 (s, 3 H), 2.37 (s, 3 H) ppm.
13C NMR ([D6]DMSO, 75 MHz): δ = 160.2, 157.8, 156.7, 147.8,
146 (br.), 145.2, 135.7, 129.8, 128.0, 127.5, 29.5, 20.9 ppm. IR (Nu-
jol mull): ν = 3410, 3300, 1638, 1600 cm–1. C H N O S (346.37)
˜
14 14
6
3
calcd. C 48.55, H 4.07, N 24.26, S 9.26; found C 48.28, H 4.15, N
23.95, S 9.00.
Method B: A solution of imidazole 1c (0.10 g, 0.67 mmol) in dry
acetonitrile (30 mL) was stirred under nitrogen in an ethylene
glycol/dry ice bath (–15 °C). After 30 min, tosyl isocyanate (0.26 g,
1.34 mmol) was added, producing an orange suspension. After
10 min at low temperature, the solid was filtered off under nitrogen
and washed with cold acetonitrile. The product was identified as 2f
(0.09 g, 0.26 mmol, 39 %). A yellow solid precipitated from the
mother liquor and was filtered and washed with acetonitrile and
diethyl ether. The product was identified as 5f (0.12 g, 0.35 mmol,
52%).
124.3, 62.8, 42.0 ppm. IR (Nujol mull): ν = 3366, 3316, 3100, 1794,
˜
1698, 1695, 1600 cm–1. C23H19N7O5·1/4 H2O (477.95) calcd. C
57.80, H 4.11, N 20.51; found C 57.90, H 4.33, N 20.75.
Method B: A solution of DBU (0.02 g, 0.14 mmol) in acetonitrile
(25 mL) was added to imidazole 2d (0.10 g, 0.22 mmol). After 4 h
at 0 °C, the solid was filtered off and washed with acetonitrile and
diethyl ether. The solid was identified as the starting material 2d
(0.03 g, 0.06 mmol, 26%). The mother liquor was stirred at 4 °C
for 6 d, but no product could be isolated because of extensive de-
composition.
General Procedure for the Synthesis of 4,4Ј-Bi-1H-imidazoles 3: A
suspension of the imidazole 2 in acetonitrile (3–6 mL) was stirred at
room temperature. Addition of DBU (0.05–0.2 molar equivalents)
resulted in an immediate change in the colour of the suspension,
which turned from yellow to orange. The mixture was stirred at
room temperature for 5 min to 2.5 h. The orange solid was filtered
off and washed with acetonitrile and diethyl ether to give com-
pounds 3a–c.
Cyclization of 2e in the Presence of Base. Method A: Imidazole 2e
(0.20 g, 0.68 mmol) was added to a solution of DBU (0.002 g,
0.01 mmol) in acetonitrile (15 mL) and the mixture was stirred at
0 °C. A different yellow suspension immediately developed and the
Ethyl 5Ј-Amino-5-imino-1Ј-(4-methoxyphenyl)-2-oxo-2,5-dihydro- mixture was stirred for 15 min. The solid was filtered off and
4,4Ј-bi-1H-imidazole-1-carboxylate (3a): Yield 0.76 mmol, 88 %;
m.p. 170 °C (dec.). H NMR ([D6]DMSO, 300 MHz): δ = 10.80 (s,
1 H), 8.00 (s, 2 H), 7.89 (s, 1 H), 7.49 (d, J = 9.0 Hz, 2 H), 7.18 (d,
washed with acetonitrile and diethyl ether. The product was iden-
tified as 3e; 0.18 g, 0.60 mmol, 88%); m.p. 236 °C (dec.). 1H NMR
([D6]DMSO, 300 MHz): δ = 10.44 (s, 1 H), 8.06 (br. s, 2 H), 7.84
1
J = 9.0 Hz, 2 H), 4.37 (q, J = 7.0 Hz, 2 H), 3.82 (s, 3 H), 1.30 (t, (d, J = 7.5 Hz, 2 H), 7.67 (s, 1 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.50
J = 7.0 Hz, 3 H) ppm. The sample was not soluble enough in [D6]-
(t, J = 7.5 Hz, 2 H), 3.50 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 167.9, 163.2, 158.6, 155.5, 153.6, 140.8, 133.6, 130.0,
DMSO for 13C NMR spectroscopy. IR (Nujol mull): ν = 3255,
˜
3200, 3090, 1750, 1712, 1646, 1623, 1614 cm–1. C16H16N6O4 129.6, 128.4, 114.2, 30.2 ppm. IR (Nujol mull): ν = 3380, 3240,
˜
(356.34) calcd. C 53.93, H 4.53, N 23.58; found C 54.05, H 4.75,
N 23.67.
1744, 1675, 1666, 1656, 1609 cm–1. C14H12N6O2·1/4H2O (300.79)
calcd. C 55.90, H 4.19, N 27.94; found C 55.95, H 4.35, N 27.69.
Ethyl 5Ј-Amino-1Ј-(2-hydroxyethyl)-5-imino-2-oxo-2,5-dihydro-4,4Ј-
bi-1H-imidazol-1-carboxylate (3b): Yield 0.28 mmol, 82 %; m.p.
199 °C (dec.). 1H NMR ([D6]DMSO, 300 MHz): δ = 10.75 (s, 1 H),
8.10 (s, 2 H), 7.65 (s, 1 H), 4.30 (q, J = 7.0 Hz, 2 H), 3.96 (t, J =
Method B: Triethylamine (0.04 g, 0.41 mmol) was added to a sus-
pension of imidazole 2e (0.12 g, 0.41 mmol) in acetonitrile (4 mL).
The mixture was stirred at room temperature for 15 min and the
yellow solid was filtered off and washed with acetonitrile and di-
5.0 Hz, 2 H), 3.63 (t, J = 5.0 Hz, 2 H), 1.28 (t, J = 7.0 Hz, 3 ethyl ether. The product was identified as 3e (0.11 g, 0.37 mmol,
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 156 (br.), 154 (br.), 90%). The mother liquor was stirred at room temperature and after
152 (br.), 150.0, 61.9, 58.4, 45.0, 14.0 ppm (the remaining signals
are not visible in the spectrum). IR (Nujol mull): ν = 3300, 3280,
one day the solvent was partially removed in the rotary evaporator
and the solid was filtered off and washed with acetonitrile and di-
˜
3180, 1741, 1646, 1602 cm–1. C11H14N6O4·1/4H2O (298.77) calcd. ethyl ether. The product was identified as purine 5e (0.005 g,
C 44.22, H 4.89, N 28.13; found C 44.05, H 4.85, N 28.11.
1932
0.02 mmol, 4%).
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1925–1934

6-Amidino-2-oxopurine Synthesis
FULL PAPER
General Procedure for the Synthesis of 2-Oxo-2,9-dihydro-1H-pu-
rine-6-carboxamidines 5 from 2. Method A: A suspension/solution
of an imidazole 2 in DMF (5–30 mL) was stirred at 0 °C to 23 °C
for 7 h–1 d. The final suspension (resulting from spontaneous pre-
cipitation of the product or from addition of water to the DMF
solution) was filtered off and washed with ethanol and diethyl ether
to give the corresponding compound 5a–d.
12 d. The yellow solid was filtered off and washed with ethanol and
diethyl ether. The product was identified as 5a (0.11 g, 0.37 mmol,
86%).
Preparation of 9-(4Ј-Methoxyphenyl)-2-oxo-2,9-dihydro-1H-purine-
6-carboxamidrazone (6). From 5a: Hydrazine hydrate (2.65 g,
2.60 mmol) was added to a suspension of 5a (0.30 g, 0.83 mmol) in
ethanol (20 mL) and the mixture was stirred at room temperature
for 18 h. The yellow suspension was filtered off and washed with
ethanol and diethyl ether, and the product was identified as 6
(0.25 g, 0.83 mmol, 99.6%); m.p. 350 °C (dec.). 1H NMR ([D6]-
DMSO, 300 MHz): δ = 10.0–8.0 (br. s, 1 H), 8.57 (s, 1 H), 7.67 (d,
J = 9.0 Hz, 2 H), 7.11 (d, J = 9.0 Hz, 2 H), 3.81 (s, 3 H) ppm. 13C
NMR ([D6]DMSO, 75 MHz): δ = 160.3, 158.6, 156.0, 146.1, 140
Method B: A suspension/solution of an imidazole 2 in ethanol (15–
50 mL) was stirred at 10 °C to 23 °C for 3–12 d. The suspension
was filtered and washed with EtOH and Et2O to give the corre-
sponding compound 5a–e.
Ethyl 6-Amidino-9-(4Ј-methoxyphenyl)-2-oxo-2,9-dihydro-1H-pu-
rine-N2-carboxylate (5a): Yield 1.06 mmol, 84%; m.p. 202–203 °C.
1H NMR ([D6]DMSO, 300 MHz): δ = 11.00–9.00 (br. s, 1 H), 8.90
(br. s, 1 H), 8.73 (s, 1 H), 7.69 (d, J = 9.0 Hz, 2 H), 7.14 (d, J =
9.0 Hz, 2 H), 4.06 (q, J = 7.0 Hz, 2 H), 3.82 (s, 3 H), 1.19 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 163.0,
160.0, 159.4, 158.9, 157.0, 146.4, 126.9, 125.9, 125.3, 114.7, 60.7,
(br.), 127.0, 125.1, 120.0, 114.5, 55.4 ppm. IR (Nujol mull): ν =
˜
3360, 3312, 3211, 1643, 1620 cm–1. MS (EI, 70 eV) m/z (rel. int.)
299 [M]+ (13). C13H13N7O2·1/4H2O (303.80) calcd. C 51.40, H
4.48, N 32.27; found C 51.67, H 4.49, N 32.37.
From 5c: Hydrazine hydrate (0.06 g, 1.16 mmol) was added to a
suspension of 5c (0.23 g, 0.58 mmol) in ethanol (20 mL) at room
temperature. After stirring for 2 d at room temperature, the yellow
solid was filtered off and washed with ethanol and diethyl ether.
The product was identified as 6 (0.17 g, 0.57 mmol, 98%).
55.6, 14.3 ppm. IR (Nujol mull): ν = 3376, 3287, 3130, 3105, 1666,
˜
1610 cm–1. MS (EI, 70 eV) m/z (rel. int.) 356 [M]+ (4). C16H16N6O4
(356.34) calcd. C 53.93, H 4.53, N 23.58; found C 53.87, H 4.51,
N 23.45.
From 5g: Hydrazine hydrate (0.10 g, 2.02 mmol) was added to a
suspension of 5g (0.34 g, 0.78 mmol) in acetonitrile (20 mL) at
room temperature. After the mixture had been stirred at room tem-
perature for 3 d, ethanol was added to precipitate the solid, which
was filtered off and washed with ethanol and diethyl ether. The
product was identified as 6 (0.18 g, 0.61 mmol, 79%).
Ethyl 6-Amidino-9-(2Ј-hydroxyethyl)-2-oxo-2,9-dihydro-1H-purine-
1
N2-carboxylate (5b): Yield 0.54 mmol, 76%; m.p. 216 °C (dec.). H
NMR ([D6]DMSO, 300 MHz): δ = 11.00–9.00 (br. s, 1 H), 8.90 (br.
s, 1 H), 8.40 (s, 1 H), 5.01 (br. s, 1 H), 4.14 (t, J = 5.0 Hz, 2 H),
4.07 (q, J = 7.0 Hz, 2 H), 3.73 (t, J = 5.0 Hz, 2 H), 1.19 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 162.8
(br.), 159.5 (br.), 158.3, 158.0, 148.7, 144.1 (br.), 124.7, 60.7, 58.7,
Synthesis of Ethyl 5Ј-Amino-1Ј-(2-hydroxyethyl)-2,5-dioxo-2,5-dihy-
dro-4,4Ј-bi-1H-imidazole-1-carboxylate (8): Trifluoroacetic acid
(0.06 g, 0.52 mmol) was added to a suspension of 3b (1.41 g,
0.50 mmol) in DMSO (1 mL) and the mixture was stirred at room
temperature. The yellow suspension turned orange immediately af-
ter the addition of the acid. No apparent change had occurred after
5 h at room temperature and the mixture was allowed to stand at
–18 °C for 2 d. The orange solid was filtered off and washed with
ethanol and diethyl ether. The product was identified as the title
compound (0.10 g, 0.33 mmol, 66%); m.p. 186 °C (dec.). 1H NMR
([D6]DMSO, 300 MHz): δ = 8.56 (br. s, 2 H), 7.59 (s, 1 H), 5.08
(br. s, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.96 (t, J = 4.8 Hz, 2 H),
3.63 (t, J = 4.5 Hz, 2 H), 1.28 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 161.0, 159.5, 155.9, 151.85, 148.3,
45.7, 14.2 ppm. IR (Nujol mull): ν = 3370, 3360, 3300, 3097, 1744,
˜
1670, 1637 cm–1. C11H14N6O4 (294.27) calcd. C 44.90, H 4.80, N
28.56; found C 44.93, H 4.79, N 28.30.
N2-Benzoyl-9-(4Ј-methoxyphenyl)-2-oxo-2,9-dihydro-1H-purine-6-
1
carboxamidine (5c): Yield 0.32 mmol, 84%; m.p. 237 °C (dec.). H
NMR ([D6]DMSO, 300 MHz): δ = 11.2 (s, 1 H), 10.0 (br. s, 1 H),
9.20 (br. s, 1 H), 8.77 (s, 1 H), 8.32 (d, J = 7.0 Hz, 2 H), 7.72 (d, J
= 9.0 Hz, 2 H), 7.58 (m, 1 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.16 (d, J
= 9.0 Hz, 2 H), 3.83 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): DBU salt, δ = 165.5, 156.2, 162.8, 157.8, 157.1, 148.8,
140.1, 133.6, 132.5, 129.0, 128.7, 128.3, 124.2, 121.8, 114.3, 55.4,
53.2, 47.8, 37.7, 31.4, 28.3, 26.0, 23.5, 19.0 ppm. IR (Nujol mull):
ν = 3360, 3200, 3170, 3120, 1640, 1620 cm–1. C H N O (388.39)
˜
20 16
6
3
142.5, 115.5, 62.9, 58.6, 45.8, 14.0 ppm. IR (Nujol mull): ν = 3582,
˜
calcd. C 61.85, H 4.15, N 21.64; found C 61.59, H 4.31, N 21.50.
3472, 3341, 1781, 1745, 1698, 1650, 1610 cm–1. C11H13N5O5·H2O
(313.27) calcd. C 42.17, H 4.83, N 22.36; found C 42.34, H 4.99,
N 21.93.
Method C: Trifluoroacetic acid (0.05 mmol; 0.006 g) was added to
a suspension of imidazole 2e (0.12 g, 0.41 mmol) in acetonitrile
(4 mL) and the mixture was stirred at room temperature for 20 min.
The suspension was filtered and washed with ethanol and diethyl
ether, and the product was identified as 5e (0.11 g, 0.38 mmol,
92%).
Acknowledgments
The authors gratefully acknowledge financial support by the Uni-
versity of Minho and Fundação para a Ciência e Tecnologia (pro-
ject PRAXIS/C/QUI/45391/2002).
Synthesis of Purine 5a from 3a. Method A: A suspension of 3a
(0.10 g, 0.29 mmol) in ethanol (15 mL) was stirred at room tem-
perature for 11 d. The yellow solid was filtered off and washed with
ethanol and diethyl ether. The product was identified as 5a (0.17 g,
0.06 mmol, 57%).
[1] M. Legraverend, D. S. Grierson, Bioorg. Med. Chem. 2006, 14,
3987–4006.
Method B: A suspension of 3a (0.08 g, 0.23 mmol) in DMF (1 mL)
was stirred at 4 °C for 23 h. The yellow solid was filtered off and
washed with EtOH and Et2O. The product was identified as 5a
(0.06 g, 0.17 mmol, 73%).
[2] a) S. Ding, N. S. Gray, Q. Ding, P. G. Schultz, J. Org. Chem.
2001, 66, 8273–8276; b) S. Ding, N. S. Gray, Q. Ding, P. G.
Schultz, Tetrahedron Lett. 2001, 42, 8751–8755.
[3] a) N. Q. Nguyen-Trung, S. Terenzi, G. Scherer, P. Strazewski,
J. Org. Chem. 2003, 68, 2038–2041; b) J. J. Bourguignon, L.
Désaubry, P. Raboisson, C. J. Wermuth, C. Lugnier, J. Med.
Chem. 1997, 40, 1768–1770; c) M. P. DeNinno, H. Masamune,
Synthesis of Purine 5e from 3e: A suspension of 3e (0.13 g,
0.44 mmol) in ethanol (15 mL) was stirred at room temperature for
Eur. J. Org. Chem. 2007, 1925–1934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1933

A. M. Dias, I. Cabral, A. S. Vila-Chã, D. S. Costa, M. F. Proença
FULL PAPER
L. K. Chenard, K. J. DiRico, C. Eller, J. B. Etienne, J. E.
Tickner, S. P. Kennedy, D. R. Knight, J. Kong, J. J. Oleynek,
W. R. Tracey, R. J. Hill, J. Med. Chem. 2003, 46, 353–355.
[4] a) J. L. Kelley, M. P. Krochmal, J. A. Linn, E. W. McLean,
F. E. Soroko, J. Med. Chem. 1988, 31, 606–612; b) J. L. Kelley,
M. P. Krochmal, J. A. Linn, E. W. McLean, F. E. Soroko, J.
Med. Chem. 1988, 31, 1005–1009.
[5] T. Higashino, S. Yoshida, E. Hayashi, Chem. Pharm. Bull.
1982, 30, 4521–4525.
[6] M. Hocek, M. Masojidkova, A. Holy, Collect. Czech. Chem.
Commun. 1995, 60, 1386–1389.
[9] a) Y. Morita, T. Murata, K. Fukui, S. Yamada, K. Sato, D.
Shiomi, T. Takui, H. Kitagawa, H. Yamagochi, G. Saito, K.
Nakasuji, J. Org. Chem. 2005, 70, 2739–2744; b) T. Murata, Y.
Morita, K. Fukui, Y. Yakiyama, K. Sato, D. Shiomi, T. Takui,
K. Nakasuji, Cryst. Growth Des. 2006, 6, 1043–1047.
[10] B. L. Booth, I. M. Cabral, A. M. Dias, A. P. Freitas, A. M.
Matos Beja, M. F. Proença, M. Ramos Silva, J. Chem. Soc.,
Perkin Trans. 1 2001, 1241–1251.
[11] A. M. Dias, I. M. Cabral, M. F. Proença, B. L. Booth, J. Org.
Chem. 2002, 67, 5546–5552.
[12] ACD/labs software Sigma Predictor 8.0.
[7] a) M. D. Cliff, S. G. Pyne, Synthesis 1994, 681–682; b) W.
Zhang, C. P. Landee, R. D. Willett, M. M. Turnbull, Tetrahe-
dron 2003, 59, 6027–6034.
[8] a) T. Murata, Y. Morita, Y. Nishimura, K. Nakasuji, Polyhe-
dron 2005, 24, 2625–2631; b) T. Murata, Y. Morita, K. Naka-
suji, Tetrahedron 2005, 61, 6056–6063; c) I. Merino, J. D.
Thompson, C. B. Millard, J. J. Schmidt, Y.-P. Pang, Bioorg.
Med. Chem. 2006, 14, 3583–3591.
[13] a) M. J. Alves, B. L. Booth, O. Kh. Al-Duaij, P. Eastwood, L.
Nezhat, M. F. Proença, A. S. Ramos, J. Chem. Res. (S) 1993,
402–403; M. J. Alves, B. L. Booth, O. Kh. Al-Duaij, P. East-
wood, L. Nezhat, M. F. Proença, A. S. Ramos, J. Chem. Res.
(M) 1993, 2701–2718; b) M. A. Carvalho, T. M. Esteves, M. F.
Proença, B. L. Booth, Org. Biomol. Chem. 2004, 2, 1019–1024.
Received: November 28, 2006
Published Online: March 2, 2007
1934
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1925–1934