Synthesis of novel 6-cyano-9-(aryl)-9H-purine derivatives via formamidine intermediates

Article abstract of DOI:10.1155/2012/762641

Novel 9-substituted cyanopurine derivatives (4a-d) were synthesized in three steps in high yield. Diaminomaleonitrile (1) reacted with triethyl orthoformate to afford (Z)-N-[2-amino-1,2-dicyanovinyl] formimidate (2) which was converted to aryl-(Z)-N-[2-am

Full text of DOI:10.1155/2012/762641

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2012, 9(1), 219-223
http://www.e-journals.net
Synthesis of Novel 6-Cyano-9-(aryl)-9H-purine
Derivatives Via Formamidine Intermediates
HASHEMI, SEYYED MILAD§*, YAHYAZADEH, ASIEH§ and NAMI, NAVABEH
§Department of Chemistry, Guilan University
P.O. Box 1914, Rasht, Guilan, Iran
Department of Chemistry, Islamic Azad University
Qaemshahr, Mazandaran, Iran
seyyedmiladhashemi@hotmail.com
Received 19 August 2010; Accepted 20 October 2010
Abstract: Novel 9-substituted cyanopurine derivatives (4a-d) were synthesized
in three steps in high yield. Diaminomaleonitrile (1) reacted with triethyl
orthoformate to afford (Z)-N-[2-amino-1,2-dicyanovinyl] formimidate (2) which
was converted to aryl-(Z)-N-[2-amino-1,2-dicyanovinyl] formamidines (3a-d)
in the presence of a catalytic amount of anilinium chloride and aromatic amines
in ethanol at room temperature under inert atmosphere (Argon). Furthermore,
the reaction of (3a-d) with triethyl orthoformate afforded novel 6-cyano-9-
(aryl)-9H-purine derivatives (4a-d) which can be used without further
purification. All compounds have been fully characterized by
spectroscopic data
.
Keywords
:
Formimidate, Aromatic amines, Formamidine, Triethyl orthoformate, 6-Cyanopurine
Introduction
Amidines are an important class of compounds which have proved to be intermediates in a
number of biological processes1-3. The chemistry and preparation of amidines have been
reviewed by Shriner and Neumann4. Purine, purine nucleosides and their analogues have
been extremely useful as an anti-cancer agents5-8. Robines, in 1964, reviewed the anti-tumour
activity of purine and purine nucleosides from a structure-activity stand-point. Subsequently
several reviews on this subject have been published9-12. Since the discovery of acyclovir
great research effort has been devoted to the synthesis of new acyclic nucleoside analogues
as potential anti-herpes (HSV) and anti-human cytomegalovirus (HCMV) agents13. The
chemotherapeutic uses of purines and purine analogues have prompted tremendous efforts
towards their synthesis, both in academia and in the pharmaceutical industry.
6-cyanopurines are usually obtained by cyanide ion substitution of either 6-iodo14, 6-tosyl-15,

220
H. SEYYED MILAD et al.
6-methyle-sulfonyl16,17 and 6-trimethylammonio18 purine derivatives, or by dehydration of
the 6-oximo derivatives with acetic anhydride19. The yields from these reactions are only
moderate to poor. It has previously reported20 that 6-cyanopurines can be obtained in good
yields by reaction of 1-substituted-5-amino-4-(cyanoformimidoyl)-imidazoles with
carboxylic acid anhydrides, but it is not always easy to isolate and handle these imidazole
intermediates and we were interested in developing a simpler route to 6-cyanopurines. In
continuation of our work on the synthesis of heterocyclic systems containing nitrogen21-26
,
we described here the synthesis of new 6-cyano-9-(aryl)-9H-purine derivatives.
Experimental
1
All solvents purified and dried using estabilished procedures. The H NMR spectra were
recorded on Bruker XL 500 (500 MHz) instruments, IR spectra on a shimadzu IR-470
spectrophotometer and mass spectra were recorded on a Kratos concept instrument. The
C, H, N analyses were performed by the micro analytical service of the N.I.O.C. Research
Institute of Petroleum Industry. The melting points were measured on an Electrothermal
digital melting point apparatus and are uncorrected.
General procedure for the preparation of the aryl-(Z)-N-[2-amino-1,2-
dicyanovinyl]formamidines (3a-d)
The aromatic amine (1.22 mmol) was added to a suspension of formimidate (2) (0.20 g,
1.22 mmol) that previously was produced27, in dry ethanol or ethylacetate (6 mL), which
contained anilinium chloride (0.01 g). The mixture was stirred at room temperature
under inert atmosphere (argon) for 9 hours. The reaction followed by TLC (8:2
ethylacetate / petroleumether) until all the formimidate (2) had disappeared and the
amidine was isolated by filtration. The most cases, the product was pale green to white.
The precipitate was washed with diethylether and air-dried to give the analytically pure
product.
4-Ethoxyphenyl-(Z)-N-[2-amino-1,2-dicyanovinyl]formamidine (3a)
(92.80%), Green, mp 148-150 oC; MS: m
/
z 255 (M)+; IR (KBr): 3450, 3350, 1470, 3100,
2950, 2210, 1630, 1590, 1375, 1465, 1280, 1240, 830 cm-1; H NMR (DMSO-d6) δ 9.83
(br.s, 1H, NH), 7.70 (d, J = 8 8Hz, 2H, Ar-H), 6.87 (d, J = 8 Hz, 2H, Ar-H), 6.37 (br.d, 2H,
NH2), 4.00 (q, J = 13.90 Hz, 2H, CH2), 3.35 (s, 1H, CH), 1.32 (t, J = 13.90 Hz, 3H, CH3).
Anal. Calcd. for C13H13N5O: C, 61.17; H, 5.10; N, 27.39. Found: C, 61.20; H, 6.56; N, 8.15.
1
1,4-Diaminophenyl-bis[(Z)-9N,9N'-(2-amino-1,2-dicyanovinyl)]formamidine (3b)
o
(71.51%), Green, mp > 340 C; MS: m
/
z 344 (M)+; IR (KBr): 3450, 3350, 3200, 2950,
2200, 1640, 1600, 1585, 1500, 1300, 1640, 810, 780 cm-1; H NMR (DMSO-d6) δ 9.97
(br.s, 1H, NH), 7.73 (s, 4H, Ar-H), 6.55 (d, J = 8.69 Hz, 1H, CH), 6.32 (br.s, 2H, NH2).
Anal. Calcd. for C16H12N2: C, 55.81; H, 3.48; N, 40.69. Found: C, 55.70; H, 3.50; N, 40.58.
1
2-Methoxybenzyl-(Z)-N-[2-amino-1,2-dicyanovinyl]formamidine (3c)
o
(65.22%), White, mp 147–150 C; MS: m
/
z 344 (M)+; IR (KBr): 3500, 3400, 3100, 2950,
2200, 1620, 1550, 1480, 1300, 1465, 1340, 850, 830 cm-1; 1H NMR (DMSO-d6) δ 7.97 (br.d,
J = 4.90 Hz, 1H, NH), 7.71 (d, J = 4.04 Hz, 1H, CH), 7.27 (q, J = 7.52 Hz, 2H, Ar-H), 7.00 (d,
J = 7.94 Hz, 1H, Ar-H), 6.91 (t, J = 7.43 Hz, 1H, Ar-H), 6.06 (s, 2H, NH2), 4.47 (d, 2H,
CH2), 3.81 (s, 3H, OCH3). Anal. Calcd. for C13H13N5O: C, 61.17; H, 5.09; N, 27.45. Found:
C, 61.20; H, 5.10; N, 27.39.

Synthesis of Novel 6-Cyano-9-(aryl)-9H-purine Derivatives
221
4-Hydroxy-(Z)-N-[2-amino-1,2-dicyanovinyl]formamidine (3d)
o
(94%), Pale green, mp 130 C; MS: m
/
z 227 (M)+; IR (KBr): 3450, 3325, 3200, 3100,
2900, 2400, 1645, 1590, 1570, 1510, 1420, 1360, 1320, 960, 820, 750 cm-1; H NMR
(DMSO-d6) δ 9.72 (s, 1H, NH), 9.22 (s, 1H, CH), 7.64 (d, 2H, Ar-H), 6.72 (s, 2H, Ar-
H), 6.28 (s, 2H, NH2). Anal. Calcd. for C11H9N5O: C, 58.14; H, 3.96; N, 30.83. Found:
C, 57.98; H, 4.01; N, 30.39.
1
General procedure for the preparation of the 6-cyano-9-(aryl)-9H-purine (4a-d)
The mixture of formamidine (3a-d) (0.40 mmol) and triethyl orthoformate (3 mL,
6.33 mmol) were heated at reflux temperature for 6 hours until TLC (8:2, ethylacetate /
petroleum ether) showed that all the formamidine (3a-d) had disappeared and the 9-substituted
cyanopurines (3a-d) was isolated by filtration. The most cases the product was grey. The
precipitate was washed with dry petroleum ether and air-dried. Obtained precipitates were
recrystallized by ethanol to give the analytically pure product.
6-Cyano-9-(4-ethoxyphenyl)-9H-purine (4a)
o
(70%), Pale gray, mp 182-184 C; MS : m
/
z 265 (M)+; IR (KBr): 3100, 2900, 2380, 1590,
1475, 1510, 1340, 1440, 1350 cm-1; H NMR (DMSO-d6) δ 9.18 (s, 1H, H (Pyrimidine)),
9.09 (s, 1H, H (Imidazole)), 7.69 (d, J = 8.89 Hz, 2H, Ar-H), 7.10 (d, J = 8.92 Hz, 2H, Ar-H),
4.07 (q, J = 6.93 Hz, 2H, CH2), 1.33 (t, J = 6.93 Hz, 3H, CH3). Anal. Calcd. for
C14H11N5O: C, 63.39; H, 4.15; N, 26.41. Found:C, 62.40; H, 4.16; N, 26.36.
1
1,4-Phenylen-bis[9N,9N'-6-cyano-9H]purine (4b)
o
(71.1%), green, mp > 340 C; MS : m
/
z 364.40 (M)+; IR (KBr): 3100, 2350, 1510, 1590,
1400, 1350 cm-1; H NMR (DMSO-d6) δ 9.41 (s, 2H, H (Pyrimidine)), 9.20 (s, 2H, H
(Imidazole)), 8.19 (s, 4H, Ar-H). Anal. Calcd. for C18H8N10: C, 59.34; H, 2.23; N, 47.45.
Found: C, 60.02; H, 2.23; N, 47.45.
1
6-Cyano-9-(2-methoxybenzyl)-9H-purine (4c)
(80.40%), Gray, mp 147-150 oC; MS : m z 293 (M)+; IR (KBr): 3100, 2900, 2380, 1590,
/
1485, 1460, 1400, 1320, 1440, 1380 cm-1; 1H NMR (CDCl3-d1) δ 9.06 (s, 1H, H
(Pyrimidine)), 8.35 (s, 1H, H (Imidazole)), 7.43 (d, J = 7.38 Hz, 1H, Ar-H), 7.35 (t, J = 7.94
Hz, 1H, Ar-H), 6.97 (t, J = 7.47 Hz, 1H, Ar-H), 6.92 (d, J = 8.28 Hz, 1H, Ar-H), 5.46 (s, 2H,
CH2), 3.87 (s, 3H, OCH3). Anal. Calcd. for C14H11N5O: C, 57.33; H, 3.75; N, 23.89. Found:
C, 56.08; H, 3.70; N, 24.07.
6-Cyano-9-(4-hydroxy)-9H-purine (4d)
(75%), Brown, mp 208-210 oC; MS: m
/
z 237 (M)+; IR (KBr): 3200, 2380, 1500, 1460, 1400,
1
1320 cm-1; H NMR (DMSO-d6) δ 10.00 (s, 1H, OH), 9.15 (s, 1H, H (Pyrimidine)), 9.11
(s, 1H, H (Imidazole)), 7.59 (d, J = 8.75 Hz, 2H, Ar-H), 6.95 (d, J = 8.79 Hz, 2H, Ar-H).
Anal. Calcd. for C12H7N5O:C, 60.75; H, 2.95; N, 29.53. Found: C, 59.90; H, 2.99; N, 29.95.
Results and Discussion
Formimidate (2) was prepared in high yield from diaminomaleonitrile (1) and triethyl
orthofarmate, according to a previously described procedure27. Having obtained the imidate (2)
in good yield it was then treated with aryl or benzylamine in a 1:1 or 1:2 molar ratio in dry
ethanol in the presence of a catalytic amount of anilinium chloride and argon atmospheres.
These compounds would be important intermediates

222
H. SEYYED MILAD et al.
for the synthesis of a range of 9-arylpurines and 9-aryl-1,2-dihydropurines. We attempted to
cyclise these amidines (3a-d) to obtain compounds (4a-d), via refluxing them with triethyl
orthofarmate (Scheme 1). The reactions followed by TLC (8:2 ethylacetate / petroleum
ether) to all the starting material had been consumed. These compounds filtered, washed
with petroleum ether and diethylether, recrystallized with ethanol. These were fully
characterized by IR, 1H-NMR, MS spectroscopy and elemental analysis.
The elemental analysis results of amidines (3a-d) were satisfactory. The infrared spectrum
of amidines (3a-d) confirmed the presence of the NH and C=N stretching vibrations in 3480-
3120 and 1600-1640 cm-1 respectively. The infrared spectrum also showed a sharp absorption
band at 2220-2200 cm-1 for the CN stretching vibration. The mass spectra showed peaks at m/z
255 (3a), 344 (3b), 255 (3c) and 227 (3d) respectively.
1
The H NMR spectra of compounds (3b) and (3c) had some interesting features. In
compound (3b) 1H NMR spectra has appeared NH proton as a broad singlet at δ=9.97 ppm,
aromatic ring protons as a singlet at δ=7.66-7.80 ppm, CH protons as a doublet at δ=6.55 ppm
1
and NH2 protons as a singlet at δ=6.32 ppm. In compound (3c) H NMR spectra has
appeared NH proton as a doublet at δ=7.96 ppm, aromatic ring protons as δ=6.6-7.30 ppm,
CH proton as a doublet at δ=7.71 ppm, NH2 protons as a singlet at δ=6.06 ppm, two benzylic
protons as a doublet at δ=4.47 ppm and OCH3 protons as a singlet at δ=3.81 ppm.
The elemental analysis results of 9-substituted cyanopurines (4a-d) were satisfactory.
The infrared spectrum of purines (4a-d) showed two strong absorptions for CN stretching
vibrations in 2350-2380 cm-1, C=N vibrations in 1510 cm-1 and C=C stretching vibration in
1400-1475 cm-1. The mass spectrums showed a peak at m/z (%) 265 (4a), 364 (4b), 293 (4c),
237 (4d) respectively.
1
The H NMR spectra of compounds (4a) and (4b) were satisfactory. In compound (4a)
1H NMR spectra has appeared CH proton of the pyrimidine as a singlet at δ=9.18 ppm, CH
proton of the imidazole as a singlet at δ=9.09 ppm, aromatic ring protons as two doublet at
δ=7.1-7.69 ppm, CH2 and CH3 protons as a quartet at δ=4.05 ppm and a triplet at δ=1.31 ppm.
In compound (4b) 1H NMR spectra has appeared CH proton of the pyrimidine, CH proton of
the imidazole, aromatic ring protons as a singlet at δ=9.41, 9.2, 8.19 respectively.
OEt
H
NH
H
R
N
R
NC
N
NC
NH2
N
RNH2, PhNH3+ Cl-
NC
N
CH(OEt)3
Reflux
1, 4 Dioxane (dry)
CH(OEt)3
+
EtOH(dry), Atmospher, r.t
NH2
NC
N
N
Reflux
NC
NH2
NC
NH2
CN
1
2
3a-d
4a-d
a: R=4-ethoxy aniline, b: R=4 amino aniline, c: R=2-methoxy benzyl amine, d: R=4-hydroxy animine
Scheme 1. Synthesis of novel 6-cyano-9(aryl)-9H-purine derivatives
Conclusion
In conclusion, a general and convenient synthesis of new 6-cyanopurine derivatives has been
developed. The main advantages of these reactions are mild reaction conditions and high
yields.The new compounds could be of interest in pharmacology and biology.

Synthesis of Novel 6-Cyano-9-(aryl)-9H-purine Derivatives
223
Acknowledgment
The authors are grateful to the Guilan University and Islamic Azad University of
Ghaemshahr for the financial support.
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