A versatile synthetic approach to isoguanine derivatives

Article abstract of DOI:10.1055/s-2007-977419

5-Amino-4-(N-ethoxycarbonyl)formamidino imidazoles were prepared from 5-amino-4-(N-ethoxycarbonyl)cyanoformimidoyl imidazoles and primary alkyl amines, under mild experimental conditions. The product imidazoles were selectively cyclized to N₆-s

Full text of DOI:10.1055/s-2007-977419

LETTER
1231
A Versatile Synthetic Approach to Isoguanine Derivatives
Synthetic
A
pproac
l
h to Iso
i
guanin
c
e
D
erivativ
e
es M. Dias, A. Sofia Vila-Chã, Isabel M. Cabral, M. Fernanda Proença*
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
E-mail: fproenca@quimica.uminho.pt
Received 8 February 2007
In our research group, 5-amino-4-cyanoformimidoyl
imidazoles 1 have been used as versatile synthons for
nitrogen heterocycles fused with the imidazole ring. The
synthesis of different 6-substituted purines15 and
Abstract: 5-Amino-4-(N-ethoxycarbonyl)formamidino imidazoles
were prepared from 5-amino-4-(N-ethoxycarbonyl)cyanoform-
imidoyl imidazoles and primary alkyl amines, under mild experi-
mental conditions. The product imidazoles were selectively
cyclized to N6-substituted isoguanines by reflux in acetonitrile with imidazopyridines16 has been reported and usually requires
one equivalent of sulfuric acid, followed by neutralization. The
same imidazoles led to N1-alkylisoguanines as the major product
upon reflux in ethanol.
mild reaction conditions. The reaction of imidazoles 1
with ethyl chloroformate led to the formation of com-
pounds 2, where the acyl group is incorporated in the imi-
ne nitrogen15g (Table 1). The electron-withdrawing effect
Key words: heterocycles, rearrangements, ring closure, imidazole,
isoguanine
of this group facilitates nucleophilic attack to the adjacent
carbon atom, and the reaction with methyl and benzyl-
amine occurred after 10 minutes to 18 hours at room tem-
Purine-based compounds display a wide range of biologi-
cal activities.1 Their potency and selectivity depends on
the position and nature of the substituents on the ring. 6-
Alkylamino-2-oxopurines have been isolated both from
higher plants and microorganisms, where they stimulate
cell division and cell growth and also delay senescence.2
Analogous structures have been synthesized, usually by
varying the side chain of the amino substituent in the 6-
position, and some of them are also active as plant growth
stimulators.3 The literature reports several methods for the
synthesis of isoguanines or isoguanosines. These
compounds were prepared from a substituted imidazole
(usually a 5-amino-4-carbamoyl imidazole4,5 or a 4,5-
dicyanoimidazole5) or from a substituted purine, in sever-
al consecutive steps. 2-Aminoadenosine,6 adenosine N-1-
oxide,7 guanosine,8 2-amino-6-chloropurine9 or 2-oxo-6-
chloropurine10 are some examples of purine compounds
that have been used in these synthesis.
perature. The products 3 were isolated as white solids in
80–89% yield.17
A suspension of compound 3 in ethanol was heated under
reflux, to induce intramolecular cyclization. A homoge-
neous solution was initially formed, leading to a different
solid suspension. When the starting material was totally
consumed (3.5 h to 4 d), the solid was filtered and identi-
fied as a mixture of purines 4 and 5. Variable ratios of
these products were obtained, depending mainly on the
reaction conditions (solvent, temperature, and time). The
experiments described in Table 1, correspond to reaction
mixtures with the highest ratio of compound 5. Com-
pounds 4 and 5 were separated using ethanol or DMF as
solvent and one equivalent of DBU (considering the
amount of isoguanine 4 present). Upon stirring the mix-
ture at room temperature, the DBU salt of 4 is solubilized,
leading to a suspension of isoguanine 5, quantitatively
recovered.18 The formation of compound 5 can only be
rationalized if the acyl substituent migrates from the imine
nitrogen to the amino group on C-5 of the imidazole ring
(Scheme 1)
1-Methylisoguanosine was isolated from several marine
sources,11 and proved to have potent muscle-relaxant ac-
tivity, and also cardiovascular and anti-inflammatory
properties.11a,12 The structure of this compound was con-
firmed by chemical synthesis, from the reaction of 5-ami-
no-4-carbamoylimidazole or 5-amino-4-cyanoimidazole
with methyl isocyanate11c,13 or from direct methylation of
isoguanosine.11b,c
R1
N
R1
N
OH
OEt
NH2
N
NH
OEt
N
N
N
NHR2
2 O
The synthesis of analogues of this pharmacologically ac-
tive compound have also been reported, and the substitu-
tion pattern was varied on N-1, N-9, and C-8, depending
on the substituted imidazole used as starting material and
on the isocyanate selected for the reaction.14
NHR
3
7
MeCN, H2SO4
reflux
EtOH
reflux
R1
N
R1
N
R1
N
OEt
O
H
N
O
N
N
O
N
NH
NHR2
NH
R2
N
N
N
NH2
NHR2
SYNLETT 2007, No. 8, pp 1231–1234
1
6.
0
5.
2
0
0
7
5
8
4
Advanced online publication: 03.04.2007
DOI: 10.1055/s-2007-977419; Art ID: G01607ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1232
A. M. Dias et al.
LETTER
Table 1 Synthesis of Purines 4 and 5
R1
N
R1
R1
N
NH2
NH2
NH
NH2
N
R2NH2
OEt
OEt
N
N
N
N
N
2 O
NHR
O
CN
CN
1a, R1 = 4-MeOC6H4
1b, R1 = 4-CNC6H4
2a, R1 = 4-MeOC6H4
2b, R1 = 4-CNC6H4
3
EtOH
reflux
MeCN, H2SO4
reflux
R1
R1
N
R1
N
N
N
O
N
O
N
O
+
NH
NHR2
N
NH·H2SO4
N
R2
N
N
NHR2
NH2
6
4
5
MeCN, DBU
Compd
3a
R1
R2
Reaction conditions
CH2Cl2, 10 min, r.t.
CH2Cl2, 30 min, r.t.
EtOH, 15 min, r.t.
MeCN, 18 h, r.t.
Yield (%)
4-MeOC6H4
4-CNC6H4
4-MeOC6H4
4-CNC6H4
4-MeOC6H4
4-CNC6H4
4-MeOC6H4
Me
Me
Bn
Bn
Me
Me
Bn
80
85
84
89
97
90
80
3b
3c
3d
4a
6a, MeCN, DBU (1 equiv), 30 min, r.t.
6b, MeCN, DBU (1 equiv), 3 h, r.t.
4b
4c
1. 3c, MeCN, H2SO4 (1 equiv), 2 d, reflux
2. DBU (1 equiv), 1 h, r.t.
4d
5a
4-CNC6H4
Bn
1. 3d, MeCN, H2SO4 (1 equiv), 11 d, reflux
2. DBU (1 equiv), 3 h, r.t.
43
4-MeOC6H4
Me
1. 3a, EtOH, 5 h, reflux
53a
2. KOH (1 N), 45 min, r.t.
5b
5c
5d
6a
6b
4-CNC6H4
4-MeOC6H4
4-CNC6H4
4-MeOC6H4
4-CNC6H4
Me
Bn
Bn
Me
Me
3b, EtOH, 9 h, reflux
31b
50c
35d
97
3c, EtOH, 3.5 h, reflux
3d, EtOH, 4 d, reflux
3a, MeCN, H2SO4 (1 equiv), 18 h, reflux
3b, MeCN, H2SO4 (1 equiv), 3 d, reflux
93
a Isolated from a mixture of 4a and 5a in a 2:8 ratio.
b Isolated from a mixture of 4b and 5b in a 3:7 ratio.
c Isolated from a mixture of 4c and 5c in a 2.5:7.5 ratio.
d Isolated from a mixture of 4d and 5d in a 2:8 ratio.
The cyclic intermediate 7 can evolve directly to isogua- ried out in acetonitrile, in the presence of one equivalent
nine 4, upon elimination of ethanol, or can ring-open, of sulfuric acid. The solid suspension was filtered when
leading to imidazole 8. This type of migration was previ- the starting material was completely consumed (18 h to
ously observed for the acetyl group, and was accelerated 11 d) leading to the hydrogenosulfate salt of isoguanine
when methanol/ethanol were used as solvents.15g Com- (6a and 6b). Direct addition of DBU (1 equiv) to the
pound 8 is postulated as the intermediate in the formation reaction mixture led to compounds 4c and 4d as the only
of isoguanine 5, formed by nucleophilic attack by the isolated products.19 Compounds 4a and 4b were also
alkylamine, in the amidine unit, to the carbonyl carbon isolated upon neutralization of the corresponding salts 6.
atom.
These reactions were carried out from N-arylimidazoles
In order to facilitate the elimination of ethanol from the with electron-withdrawing (R1 = 4-CNC6H4) and elec-
cyclic intermediate 7, the reflux of imidazole 3 was car- tron-donating (R1 = 4-MeOC6H4) substituents. Longer
Synlett 2007, No. 8, 1231–1234 © Thieme Stuttgart · New York

LETTER
Synthetic Approach to Isoguanine Derivatives
1233
(12) (a) Baird-Lambert, J.; Marwood, J. F.; Davies, L. P.; Taylor,
K. M. Life Sci. 1980, 26, 1069. (b) Davies, L. P.; Taylor, K.
M.; Gregson, R. P.; Quinn, R. J. Life Sci. 1980, 26, 1079.
(c) Davies, L. P.; Cook, A. F.; Poonian, M. S.; Taylor, K. M.
Life Sci. 1980, 26, 1089.
(13) (a) Grozinger, K.; Freter, K. R.; Farina, P.; Gladczuk, A.
Eur. J. Med. Chem. 1983, 18, 221. (b) Nachman, R. J.
J. Heterocycl. Chem. 1985, 22, 953. (c) Grozinger, K. G.;
Onan, K. D. J. Heterocycl. Chem. 1986, 23, 737.
reaction times were usually required when the 1-(4-
cyanophenyl)imidazoles 3b or 3d were used as starting
material. This may be due to the poor solubility of these
compounds in the reaction solvent or to a reduced nucleo-
philicity of the amino group in the 5-position, as a result
of the electron-withdrawing effect of the aromatic sub-
stituent. Nevertheless, the yields are usually very good
except for the formation of compound 4d. This reaction
was particularly slow (11 d under reflux in acetonitrile
and 1 equiv of sulfuric acid) leading to extensive degrada-
tion of the reaction mixture and a poor isolated yield of the
product (43%).
(14) Bartlett, R. T.; Cook, A. F.; Holman, M. J.; McComas, W.
W.; Nowoswait, E. F.; Poonian, M. S. J. Med. Chem. 1981,
24, 947.
(15) (a) Alves, M. J.; Booth, B. L.; Freitas, A. P.; Proença, M. F.
J. Chem. Soc., Perkin Trans. 1 1992, 913. (b) Booth, B. L.;
Dias, A. M.; Proença, M. F. J. Chem. Soc., Perkin Trans. 1
1992, 2119. (c) Alves, M. J.; Booth, B. L.; Proença, M. F.
J. Heterocycl. Chem. 1994, 31, 345. (d) Booth, B. L.;
Coster, R. D.; Proença, M. F. Synthesis 1988, 389.
(e) Alves, M. J.; Booth, B. L.; Carvalho, M. A.; Pritchard, R.
G.; Proença, M. F. J. Heterocycl. Chem. 1997, 739. (f) Al-
Azmi, A.; Booth, B. L.; Carpenter, R. A.; Carvalho, M. A.;
Marrelec, E.; Pritchard, R. G.; Proença, M. F. J. Chem. Soc.,
Perkin Trans. 1 2001, 2532. (g) Booth, B. L.; Cabral, I. M.;
Dias, A. M.; Freitas, A. P.; Matos-Beja, A. M.; Proença, M.
F.; Ramos-Silva, M. J. Chem. Soc., Perkin Trans. 1 2001,
1241. (h) Carvalho, M. A.; Esteves, T. M.; Proença, M. F.;
Booth, B. L. Org. Biomol. Chem. 2004, 2, 1019.
In conclusion, an easily accessible substituted imidazoles
2 were used as the precursor of imidazoles 3, formed at
room temperature and in the presence of a primary alkyl
amine. Compounds 3 were cyclized either to N1-alkyl-
isoguanines 5 or N6-substituted isoguanines 4, depending
on the reaction conditions used. These compounds, which
are not easily prepared by other methods, were isolated in
very good yields from this common intermediate.
Acknowledgment
The authors gratefully acknowledge the financial support by the
University of Minho and Fundação para a Ciência e Tecnologia
(project PRAXIS/C/QUI/45391/2002).
(i) Carvalho, M. A.; Álvares, Y.; Zaki, M. E.; Proença, M.
F.; Booth, B. L. Org. Biomol. Chem. 2004, 2, 2340.
(16) (a) Dias, A. M.; Cabral, I. M.; Proença, M. F.; Booth, B. L.
J. Org. Chem. 2002, 67, 5546. (b) Zaki, M. E.; Proença, M.
F.; Booth, B. L. J. Org. Chem. 2003, 68, 276 .
References and Notes
(17) Compounds 3
Aqueous methylamine (for 3a and 3b, 14 equiv), or
benzylamine (for 3c and 3d, 2–3 equiv) was added to a
suspension of imidazole 2 in CH2Cl2 (for 3a and 3b), EtOH
(for 3c), or MeCN (for 3d, 2–12 mL). The mixture was
stirred at r.t. for 10 min to 18 h. The product precipitated
from the reaction mixture (3c and 3d) or the solvent was
removed in the rotary evaporator (3a and 3b) and EtOH was
added to the residue. The white solid was filtered and
washed with EtOH (3a–c), or MeCN(3d), and Et2O. The
structure of the products obtained was confirmed by
elemental analysis, 1H NMR and 13C NMR spectroscopy.
Characterization of 3a
(1) For a recent review, see: Legraverend, M.; Grierson, D. S.
Bioorg. Med. Chem. 2006, 14, 3987.
(2) (a) Farooqi, A. H. A.; Shukla, Y. N.; Shukla, A.; Bhakuni, D.
S. Phytochemistry 1990, 29, 2061. (b) Dahiya, J. S.; Tewari,
J. P. Phytochemistry 1991, 30, 2825. (c) Fujii, T.; Ohba, M.;
Kawamura, H.; Haneishi, T.; Matsubara, S. Chem. Pharm.
Bull. 1993, 41, 1362.
(3) (a) Hecht, S. M.; Leonard, N. J.; Schmitz, R. Y.; Skoog, F.
Phytochemistry 1974, 13, 329. (b) Chen, C.-M.; Smith, O.
C.; McChesney, J. D. Biochemistry 1975, 14, 3088.
(4) (a) Yamazaki, A.; Okutsu, M.; Yamada, Y. Nucleic Acids
Res. 1976, 3, 251. (b) Yamazaki, A.; Okutsu, M.
J. Heterocycl. Chem. 1978, 15, 353. (c) Chern, J.-W.; Lee,
H.-Y.; Huang, M.; Shish, F. J. Tetrahedron Lett. 1987, 28,
2151.
(5) Yamazaki, A.; Kumashiro, I.; Takenishi, T.; Ikehara, M.
Chem. Pharm. Bull. 1968, 2172.
(6) Davoll, J. J. Am. Chem. Soc. 1951, 73, 3174.
(7) Cramer, F.; Schlingloff, G. Tetrahedron Lett. 1964, 13,
3201.
(8) Nair, V.; Young, D. A. J. Org. Chem. 1985, 50, 406.
(9) Divakar, K. J.; Mottahedeh, M.; Reese, C. B.; Sanghvi, Y.
S.; Swift, K. A. D. J. Chem. Soc., Perkin Trans. 1 1991, 771.
(10) De Napoli, L.; Montesarchio, D.; Piccialli, G.; Santacroce,
C.; Varra, M. J. Chem. Soc., Perkin Trans. 1 1995, 15.
(11) (a) Fuhrman, F. A.; Fuhrman, G. J.; Kim, Y. H.; Pavelka, L.
A.; Moshee, H. S. Science 1980, 207, 193. (b) Quinn, R. J.;
Gregson, R. P.; Cook, A. F.; Bartlett, R. T. Tetrahedron Lett.
1980, 21, 567. (c) Cook, A. F.; Bartlett, R. T.; Gregson, R.
P.; Quinn, R. J. J. Org. Chem. 1980, 45, 4020.
1H NMR (300 MHz, DMSO-d6, 20 °C): d (mixture of
conformers A and B, ratio A/B = 3:2) = 9.90 (br s, 1 H, A),
8.00 (br s, 1 H, B), 7.40 (d, J = 9.0 Hz, 2 H), 7.39 (s, 1 H),
7.12 (d, J = 9.0 Hz, 2 H), 6.94 (br s, 2 H, A), 5.98 (br s, 2 H,
B), 3.97 (q, J = 7.2 Hz, 2 H), 3.81 (s, 3 H), 3.41 (s, 3 H, A),
2.74 (s, 3 H, B), 1.17 (t, J = 7.2 Hz, 3 H); 1H NMR (300
MHz, DMSO-d6, 50 °C): d (only one set of bands is
present) = 10.20–9.20 (br s, 1 H), 7.37 (d, J = 8.7 Hz, 2 H),
7.34 (s, 1 H), 7.11 (d, J = 8.7 Hz, 2 H), 6.80–6.30 (br s, 2 H),
3.99 (q, J = 7.2 Hz, 2 H), 3.82 (s, 3 H), 3.20 (s, 3 H), 1.18 (t,
J = 7.2 Hz, 3 H). 13C NMR (75 MHz, DMSO-d6): d = 163.49
(br, A), 159.20, 156.80 (br, B), 147.08 (br), 142.70, 130.99,
126.91, 126.72, 114.99, 110.00–114.00 (br), 59.47 (br),
55.55, 32.31 (br, A), 23.45 (br, B), 14.68. Anal. Calcd for
C15H19N5O3: C, 56.77; H, 6.04; N, 22.07. Found: C, 56.97;
H, 6.06; N, 21.57. IR (mull): 3251 (m), 3116 (m), 1640 (s),
1598 (s).
(18) Compounds 5
A suspension of 3a–d in EtOH (20–60 mL) was refluxed for
5 h to 4 d. The resulting suspension was filtered and washed
with MeCN (4 and 5a), EtOH (4 and 5b and d) or Et2O (4
and 5c) to give a mixture of compounds 4 and 5 in a ratio of
Synlett 2007, No. 8, 1231–1234 © Thieme Stuttgart · New York

1234
A. M. Dias et al.
LETTER
4.5:5.5 (4a:5a), 3:7 (4b:5b), 2.5:7.5 (4c:5c) and 2:8 (4d:5d).
The mixture 4a:5a (4.5:5.5) was suspended in H2O and
combined with KOH (1 N). The suspension was stirred at r.t.
for 45 min to give a 2:8 mixture of 4a:5a. A suspension of
these solid mixtures in EtOH (for a and c) or DMF (for b and
d) was combined with DBU (1 equiv in relation to the
amount of compound 4). The suspension was stirred at 40 °C
for 6–18 h (a and b), or at r.t. for 30 min (c and d). The white
solid was filtered and washed with EtOH and Et2O to give
compound 5a–d. The structure of the products obtained was
confirmed by elemental analysis, 1H NMR and 13C NMR
spectroscopy.
(19) Compounds 4
To a suspension of imidazole 3a–d in MeCN (8–10 mL) was
added H2SO4 (1 equiv), and the mixture was refluxed for
18 h to 11 d. The resulting suspension was filtered and
washed with MeCN (6a) or EtOH (6b) and Et2O. Then,
DBU (1 equiv) was added to a suspension of compound 6a,b
in MeCN (3–20 mL). The mixture was stirred at r.t. for 30
min to 3 h, when the white solid was filtered and washed
with MeCN and Et2O, to give compounds 4a,b. The
structure of the products obtained was confirmed by
elemental analysis, 1H NMR and 13C NMR spectroscopy.
Characterization of 4a
Characterization of 5a
1H NMR (300 MHz, DMSO-d6): d = 10.70 (v br s, 1 H), 8.08
(s, 1 H), 8.00 (br s, 1 H), 7.64 (d, J = 9.0 Hz, 2 H), 7.08 (d,
J = 9.0 Hz, 2 H), 3.80 (s, 3 H), 2.93 (br s, 3 H). The
compound 4a was not soluble in DMSO-d6 and the 13C NMR
spectrum was obtained from the salt form. 13C NMR (75
MHz, DMSO-d6): d = 160.16, 151.85, 149.94, 141.98,
139.87, 127.31, 125.55, 115.10, 110.62, 55.86, 29.25. Anal.
Calcd for C13H13N5O2·0.4H2O: C, 56.07; H, 4.99; N, 25.15.
Found: C, 55.95; H, 4.92; N, 25.12. IR (mull): 3234 (s), 3126
(m), 3053 (m), 2733 (m), 1681 (s), 1626 (s), 1596 (s).
1H NMR (300 MHz, DMSO-d6): d = 8.16 (br s, 2 H), 8.07 (s,
1 H), 7.66 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 9.0 Hz, 2 H), 3.80
(s, 3 H), 3.36 (s, 3 H). 13C NMR (75 MHz, DMSO-d6): d =
158.03, 154.18, 152.39, 151.49, 137.66, 128.13, 124.35,
114.36, 109.00–110.00(br), 55.06, 30.01. Anal. Calcd for
C13H13N5O2: C, 57.56; H, 4.83; N, 25.82. Found: C, 57.60;
H, 5.06; N, 25.78. IR (mull): 3385 (m), 3208 (s), 3120 (s),
3052 (s), 1883 (w), 1698 (s), 1640 (s), 1601 (s), 1584 (s).
Synlett 2007, No. 8, 1231–1234 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.