Synthesis of 9-aryl-6-aminopurines from 5-amino-1-aryl-1H-imidazole-4- carbonitriles

Article abstract of DOI:10.1023/B:RUJO.0000013141.59809.a3

5-Amino-1-aryl-1H-imidazole-4-carbonitriles were converted into 9-aryl-6-aminopurines via imidates formation at treating with CH(OEt) ₃ and Ac₂O followed by reaction with ammonia.

Full text of DOI:10.1023/B:RUJO.0000013141.59809.a3

Russian Journal of Organic Chemistry, Vol. 39, No. 11, 2003, pp. 1649 1651. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 11, 2003,
pp. 1718 1720.
Original Russian Text Copyright
2003 by Yahya-Zadeh.
Synthesis of 9-Aryl-6-aminopurines
from 5-Amino-1-aryl-1H-imidazole-4-carbonitriles
A. Yahay-Zadeh
Chemical Department, Guilan University, Iran
Received May 6, 2002
Abstract 5-Amino-1-aryl-1H-imidazole-4-carbonitriles were converted into 9-aryl-6-aminopurines via
imidates formation at treating with CH(OEt)3 and Ac2O followed by reaction with ammonia.
Purine, purines nucleosides, and their analogs are
valuable antitumor medicines [1 4]. In 1964 Robins
considered in a review the antitumor activity of the
purine and purine nucleosides from the viewpoint of a
structure activity relation [5]. Several reviews on
this problem were published later [6 9]. The chemo-
therapeutic application of purines and their analogs
encouraged the growth of research on their synthesis
both in theoretical aspect and in pharmaceutical
industry.
ed in a vacuum, the residue was treated with a mix-
ture of ethyl ether hexane, 1: 1, and thus imidate II
was prepared in good yield. Compound IIa was used
in the next stage without additional purification; all
the other imidates II were recrystallized from ethyl
ether hexane (1: 1).
In all cases (again except compound IIa) the
results of microanalysis and mass spectrometry were
satisfactory. In the IR spectra of compounds IIb d
the absorption bands of stretching vibrations of C N
and C=N groups were observed at 2210 2220 and
1-Amino-6-iminopurines and 6-hydrazinopurines
are potential chemotherapeutical agents which are
poorly understood up till now [10, 11]. We used the
transformations shown further in the synthesis of
9-arylpurines.
1
1630 1650 cm respectively.
1
In the H NMR spectra of ethoxyimidates IIb d
the signal of proton H2 from the imidazole ring
appeared in the region
7.26 8.28 ppm, that of
proton H7 at 8.28 8.66 ppm. The accurate quartet
and triplet from CH2 and CH3 groups of the ethoxy
substituent were observed respectively as expected at
4.31 4.50 and 1.32 1.55 ppm.The other signals were
in conformity with the assumed structures of com-
pounds IIb d. The 13C NMR spectra of imidazoles
IIb d also contained the expected set of signals: peak
from carbon C2 of the imidazole ring appeared at
135 140.9, of carbon C7 at 159.9 165.5, and of
carbon C4 at 98.9 103.0 ppm.
Imidates IIa d were converted into the cor-
responding 6-amino-9-arylpurines IIIa d by treating
with ammonia in a minimum amount of methanol.
The reactions were carried out at room temperature
under argon atmosphere. Within the first 20 min of
reaction started precipitation of a white solid.
In 2 3 h TLC monitoring revealed the absence of the
initial reagent, The reaction mixture was filtered to
isolate the powder product in 67 93% yield. Purines
IIIa d were characterized by microanalysis and
spectral methods. The elemental analyses and mass
spectra of 6-amino-9-arylpurines IIIa d were
adequate.
R = 2-ClC6H4CH2 (a), 3,4-(CH3O)2C6H3CH2 (b),
3,4-(CH3O)2C6H3 (c), 4-CH3OC6H4 (d).
The initial stage involved the conversion of
5-amino-1H-imidazole-4-carbonitriles [12, 13] into
the corresponding ethoxyimidates IIa d. This was
performed with the use of procedure [14, 15] modifi-
ed by heating the appropriate cyanoamine with tri-
ethyl orthoformate for several hours.
After complete consumption of the initial reagent
(TLC monitoring) the solution obtained was evaporat-
1070-4280/03/3911-1649$25.00 2003 MAIK Nauka/Interperiodica

1650
YAHAY-ZADEH
In the IR spectra the stretching vibrations of NH
149.5 (C5), 116.1 (C6), 159.9 (C7), 14.0 (C9), 47.8
(C10), 55.9 and 56.0 (C17 and C18), 63.9 (C8), 110
and 111.4 (C13 and C16), 120.4 (C12), 127.5 (C11).
Found, %: C 59.8; H 5.5; N 18.4. C16H18N4O3. Cal-
culated, %: C 60.0; H 5.3; N 18.7. Mass spectrum,
m/z: 315 (M + 1)+ . Mcalc 314.
groups were observed as 3 4 bands in the region
1
3300 3095 cm , and the absorption of C=N bonds
1
appeared in the region 1660 1650 cm . In the
1H NMR spectra the proton signals from NH2 group
were located in the region 5.68 5.94 ppm, the peak
of proton H2 from purine system appeared at 8.18
8.50 ppm, and the proton H8 gave rise to a singlet at
8.08 8.38 ppm.
1-(3,4-Dimethoxyphenyl)-5-[(ethoxymethylid-
ene)amino]-1H-imidazole-4-carbonitrile (IIc). On
recrystallization of the reaction product from a mix-
ture ethyl ether hexane (1: 1) we obtained 0.48 g
(79%) of compound IIb as pale yellow crystals, mp
EXPERIMENTAL
1
104 106 C. IR spectrum, , cm : 2215 s (C N),
1H NMR spectra were registered on spectrometers
Hitachi Perkin Elmer R24B (60 MHz) or Bruker XL
300 (300 MHz). Coupling constants J are given in Hz.
13C NMR spectra (in DEPT 125 mode) were measur-
ed on spectrometer Bruker WP80 or Bruker XL 300.
IR spectra were recorded on spectrophotometer
Shimadzu IR-435. Mass spectra were taken on Kratos
Concept instrument. Melting points were measured
on a digital device Electrothermal and were reported
uncorrected.
1
1630s (C=N). HNMR spectrum, , ppm: 8.28(H2),
8.70(H), 4.50(H), 1.55(H), 4.03s (3H, OMe), 4.05 s
3
4
(3H, OMe), 7.30d.d (1H, H11, J11,12 8, J11,15 2Hz),
7.38 d (1H, H12, J12,11 8 Hz), 7.42 d (1H, H15, J15,11
2 Hz). 13C NMR spectrum, , ppm: 140.9 (C2),
103.0 (C4), 149.6 (C5), 120.2 (C6), 165.5 (C7), 17.9
(C9), 49.9 (C16 and C17), 67.8 (C8), 113.5 and
115.7 (C12 and C15), 121.3 (C11), 131.0 (C10), 152.9
(C13 and C14). Found, %: C 59.8; H 5.5; N 18.4.
C15H16N4O3. Calculated, %: C 60.0; H 5.3; N 18.7.
Mass spectrum, m/z: 301 (M + 1)+ . Mcalc 300.
3
4
1-Aryl-5-[(ethoxymethylidene)amino]-1H-imid-
azole-4-carbonitriles IIa d. A mixture of 5-amino-1-
aryl-4-cyanoimidazole (0.5 g), triethyl orthoformate
(1 mol-equiv) and acetic anhydride (6 mol-equiv) was
cautiously heated to 60 70 C for several hours under
argon atmosphere. On completion of initial product
consumption (TLC monitoring) the obtained yellow-
brown solution was evaporated in a vacuum. The
residue was treated with a mixture of anhydrous ether
and hexane (1: 1). The separated precipitate was
filtered off, washed with the same solvent mixture,
and dried in a vacuum.
1-(4-Methoxyphenyl)-5-[(ethoxymethylidene)-
amino]-1H-imidazole-4-carbonitrile (IId). On re-
crystallization of the reaction product from a mixture
ethyl ether hexane (1: 1) we obtained 0.54 g (86%)
of compound IIb as pale colorless crystals, mp 82
1
83 C. IR spectrum, , cm : 2220 s (C N), 1650 s
(C=N). 1H NMR spectrum, , ppm: 8.10 (H2),
8.55 (H7), 4.34 (H8), 1.38 (H9), 3.94 (OMe), 7.22 d
3
(2H,3H12 and H14, J12,11 9 Hz), 7.54 d (2H, H11 and
9
H15, J11,12 Hz). 13C NMR spectrum, , ppm: 140.6
(C2), 102.8 (C4), 149.5 (C5), 120.0 (C6), 165.3 (C7),
17.7(C9), 59.4 (C16), 67.7 (C8), 118.4 (C12 and C14),
130.7 (C11 and C15), 131.1 (C10), 163.1 (C13). Found,
%: C 62.3; H 5.2; N 20.7. C14H14N4O2. Calculated,
%: C 62.2; H 5.2; N 20.7. Mass spectrum, m/z: 271
(M + 1)+ . Mcalc 270.
1-(2-Chlorobenzyl)-5-[(ethoxymethylidene)-
amino]-1H-imidazole-4-carbonitrile
(IIa).
On
evaporation of the yellow-brown solution in a vacuum
an oily compound was obtained which was used in
the second stage of reaction without further purifica-
tion.
6-Amino-9-arylpurines IIIa d. To a stirred solu-
tion of 1-aryl-4-cyano-5-[(ethoxymethylene)amino]-
imidazole IIa d (0.3 g) in anhydrous methanol (8
10 ml) was added under argon atmosphere at room
temperature 1 mol-equiv of ammonia. In 15 20 min
the separated precipitate was filtered off, washed with
a mixture of anhydrous ethyl ether hexane (1: 1), and
dried in a vacuum.
1-(3,4-Dimethoxybenzyl)-5-[(ethoxymethylidene)-
amino]-1H-imidazole-4-carbonitrile (IIb).
On
recrystallization of the reaction product from a mix-
ture ethyl ether hexane (1: 1) we obtained 0.53 g
(87%) of compound IIb as pale yellow crystals, mp
1
87 88 C. IR spectrum, , cm : 2210 s (C N), 1635
(C=N). 1H NMR spectrum (DMSO-d6), , ppm:
7.26 (H2), 8.30 (H7), 4.31 (H8), 1.32 (H9), 3.78 (2
OMe), 3.80 s (3H, OCH3), 4.90 s (2H, H10), 6.62 d
6-Amino-9-(2-chlorobenzyl)purine (IIIa). Along
the above procedure compound IIIa was obtained as
colorless solid. After recrystallization from a mixture
of anhydrous ethyl ether with hexane (1: 1) we obtain-
ed crystalline compound IIIa in 67% yield, mp 168
4
3
(1H, H16, J12,16 2 Hz), 6.68 d.d (1H, H12, J12,13 8,
4J12,16 2 Hz), 6.78 d (1H, H13, J13,12 8 Hz).
3
13C NMR spectrum, , ppm: 135.4 (C2), 98.9 (C4),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 11 2003

SYNTHESIS OF 9-ARYL-6-AMINOPURINES
1651
1
170 C. IR spectrum, cm : 3300 m, 3285 s, 3150 m,
6-Amino-9-(4-methoxyphenyl)purine (IIId).
Along the above procedure compound IIId was
obtained as colorless solid. After recrystallization
from a mixture of anhydrous ethyl ether with hexane
(1: 1) we obtained 0.24 g (93%) of colorless crystals
of compound IIId, mp 197 199 C. IR spectrum,
3140 s, 3095 s (N H); 1650 s (C=N), 1600 s
(N H). H NMR spectrum, , ppm: 8.26 (H2), 8.22
1
(H8), 5.68 (H10), 5.94 (NH2), 7.25 d.d (1H, H16,
3J16,15 7, J16,14 1 Hz), 7.63 7.60 d.d.t (2H, H14 and
4
H15, J14,16 2, J14,13 8 Hz), 7.8 d.d (1H, H13, J13,14
4
3
3
1
cm : 3310 br, 3260 s, 3185 s, 3120 m (N H);
7, J13,15 1 Hz). 13C NMR spectrum, , ppm: 152
4
1
1650 s (C=N), 1600 s (N H). H NMR spectrum,
(C2), 146 (C4), 126 (C5), 158.2 (C6), 144 (C8), 48.5
(C10), 131.8 (C15), 133.1 (C16), 133.7 (C14), 133.8
(C13), 136.0 (C12), 138.0 (C11). Found, %: C 55.6;
H 4.1; N 27.4; Cl 13.1. C12H10N5Cl. Calculated, %:
C 55.6; H 3.9; N 27.0; Cl 13.5. Mass spectrum, m/z:
(M + 1)+ 260. Mcalc 259.
, ppm: 8.50 (H), 8.38 (H), 5.82 (H), 3.98 (OMe),
3
7.20 d (2H, H12 and H13, J12,11 8.5 Hz), 8.10 d (2H,
3
H11 and H14, J11,12 8.5 Hz). 13C NMR spectrum, ,
ppm: 153 (C2), 147 (C4), 130 (C5), 163.2 (C6), 143
(C8), 59.6 (C15), 118.7 (C12 and C14), 129.5 (C11 and
C15), 132.9 (C10), 166.4 (C13). Found, %: C 59.5;
H 4.6; N 28.9. C12H11N5O. Calculated, %: C 59.8;
H 4.6; N 29.0. Mass spectrum, m/z: 242 (M + 1)+ .
Mcalc 241.
6-Amino-9-(3,4-dimethoxybenzyl)purine (IIIb)
was obtained as colorless solid. After recrystallization
from a mixture of toluene with ethanol (1: 1) we
obtained 0.22 g (83%) of colorless crystals of com-
1
REFERENCES
pound IIIb, mp 172 174 C. IR spectrum, cm :
3300 s, 3210 m, 3100 s (N H); 1660 (C=N),
1605 m (N H). H NMR spectrum, , ppm: 8.18
1
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(H), 810 (H), 5.25 (H), 5.72 (H), 3.78 (2 OMe),
3
6.86 d (1H, H13, J13,12 8 Hz), 6.95 d.d (1H, H12,
4
4
3J12,13 8, J12,16 2 Hz), 7.12 d (1H, H16, J16,12
2 Hz). 13C NMR spectrum, , ppm: 152 (C2), 145
(C4), 126 (C5), 158.2 (C6), 143 (C8), 50.3 (C10),
59.6 (C17 and C18), 115.7, 115.9, 124.1 (C12, C13
and C16), 133.3 (C11), 152.5 and 152.8 (C14 and
C15). Found, %: C 58.7; H 5.2; N 24.5. C14H15N5O2.
Calculated, %: C 58.9; H 5.3; N 24.6. Mass spec-
trum, m/z: 286 (M + 1)+ . Mcalc 285.
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6-Amino-9-(3,4-dimethoxyphenyl)purine (IIIc)
was obtained in the same way as colorless solid. After
recrystallization from a mixture of toluene with
ethanol (1: 1) we obtained 0.23 g (85%) of colorless
crystals of compound IIIc, mp 190 192 C. IR spec-
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1
trum, cm : 3290 m, 3230 s, 3110 m (N H); 1655 s
(C=N), 1605 m (N H). 1H NMR spectrum,
,
ppm: 8.26 (H), 8.08 (H), 5.68 (H), 3.78 (2 OMe),
4
7.08 d (1H, H15, J15,11 2 Hz), 7.20 d.d (1H, H11,
4
3
3J11,12 8, J11,15 2 Hz), 7.28 d (1H, H12, J12,11 8 Hz).
13C NMR spectrum, , ppm: 152 (C2), 145 (C4), 127
(C5), 160 (C6), 143 (C8), 59.8 (C16 and C17), 112.1
(C15), 115.9 (C12), 119.8 (C11), 131.6 (C10), 135.0
(C13), 152.1 (C14). Found, %: C 57.5; H 4.8; N 25.4.
C13H13N5O12. Calculated, %: C 57.6; H 4.8; N 25.8.
Mass spectrum, m/z: 272 (M + 1)+ . Mcalc 271.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 11 2003