Synthesis of 5-amino-1-aryl-4-cyanoimidazoles from N-aryl-N′-(1,2-dicyanovinyl)-formamidines

Article abstract of DOI:10.1081/SCC-100106031

The aryl-(Z)-N-[2-amino-1,2-dicyanovinyl]formamidine cyclize in the presence of base to give a 1,5-diamino-4-cyanoimidazole or a 1,5-diamino-4-(cyanoformimidoyl)imidazole, depending on the reaction conditions and the nature of the base used to induced cyc

Full text of DOI:10.1081/SCC-100106031

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SYNTHESIS OF 5-AMINO-1- ARYL-4-CYANOIMIDAZOLES
FROM N-ARYL-N′-(1,2-DICYANOVINYL)-
FORMAMIDINES
Asieh Yahya-Zadeh a & Brian L. Booth b
a Department of Chemistry , University of Guilan , P.O. Box 1914, Rasht, Iran
b Department of Chemistry , University of Manchester Institute of Science and
Technology , Manchester, M60 1QD, UK
Published online: 20 Aug 2006.
To cite this article: Asieh Yahya-Zadeh & Brian L. Booth (2001) SYNTHESIS OF 5-AMINO-1- ARYL-4-CYANOIMIDAZOLES
FROM N-ARYL-N′-(1,2-DICYANOVINYL)- FORMAMIDINES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:21, 3225-3230, DOI: 10.1081/SCC-100106031
To link to this article: http://dx.doi.org/10.1081/SCC-100106031
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SYNTHETIC COMMUNICATIONS, 31(21), 3225–3230 (2001)
SYNTHESIS OF 5-AMINO-1-
ARYL-4-CYANOIMIDAZOLES FROM
N-ARYL-N 0-(1,2-DICYANOVINYL)-
FORMAMIDINES
2
Asieh Yahya-Zadeh1, andBrian L. Booth
*
1Department of Chemistry, University of Guilan,
P.O. Box 1914, Rasht, Iran
2Department of Chemistry, University of Manchester
Institute of Science and Technology,
Manchester M60 1QD, UK
ABSTRACT
The aryl-(Z )-N-[2-amino-1,2-dicyanovinyl]formamidine cyc-
lize in the presence of base to give a 1,5-diamino-4-cyano-
imidazole or a 1,5-diamino-4-(cyanoformimidoyl)imidazole,
depending on the reaction conditions and the nature of the
base used to induced cyclization.
5-Amino-4-cyanoimidazoles have long been recognized as useful syn-
thetic precursors for compounds such as a series of biologically active
purines and their derivatives, but there is no simple, general synthesis
available for 1-aryl derivatives of these compounds.
*Corresponding author.
3225
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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YAHYA-ZADEH AND BOOTH
Preparation of 5-amino-4-cyano-l-( p-aminosulfonylphenyl)imidazole
was reported via a multistep synthesis from the corresponding 1-methyl
derivative.1 Frank and Zeller have described the synthesis of a number of
1-aryl and 1-heteroaryl derivatives in low to moderate yield by reaction of
the corresponding ethyl N-substituted formimidates with 2-aminomalononi-
trile toluene-p-sulfonate in acetic acid.2 We have been developing new routes
to 5-amino-1-aryl-4-cyanoimidazoles (2) from corresponding cyanoformimi-
doyl imidazoles (3) by treatment with aqueous KOH solution.3
The same compounds (3) can also be synthesised directly from the
corresponding amidines (2) under similar strongly basic conditions. We
thus attempted to cyclise the aromatic amidines (2a–2d) to obtain com-
pounds of type (3a–3d), which would be important intermediates for the
synthesis of a range of 9-arylpurines and 9-aryl-1,2-dihydropurines.4,5
Scheme 1. Reagents and conditions; i, HC(OEt)3, dioxane, heat; ii, RNH2,
PhNHþ3 Clꢀ, room temp., 3–4 h; iii, 1 mol dmꢀ3 KOH, aq. room temp.
The preparation of 5-amino-1-aryl-4-cyanoimidazoles (3a–3d) were
attempted from the corresponding amidines (2a–2d) in the presence of an
aqueous potassium hydroxide solution (1 M) at room temperature. Imidate
(1) was prepared in high yield from diaminomaleonitrile and triethyl ortho-
formate, according to a previously described procedure.6–8 Having obtained
the imidate (1) in good yield (94%) it was then treated with aryl or benzyl-
amine in a 1 : 1 molar ratio in ethanol in the presence of a catalytic amount
of anilinium hydrochloride.4 The cyanoimidazoles (3a–3d) were isolated in
good yields.
Compounds (3a–3d) were recrystallised from mixture of ethanol/
methanol (1 : 1) and gave pale yellow to off white crystals respectively.

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5-AMINO-1-ARYL-4-CYANOIMIDAZOLES
3227
These were fully characterized by microanalysis, IR, 1H and 13C NMR
spectroscopy and mass spectrometry. The infrared spectrum confirmed the
presence of the NH and C¼N stretching vibrations within the region of
3460–3140 (3–4 bands), and 1655–1650 cmÀ1 respectively. The infrared spec-
trum also showed a sharp absorption band within the range of
1
2200–2240 cmÀ1 for the CꢀN stretching vibration. In the H NMR spectra
of the isolated 5-amino-1-aryl-4-cyanoimidazoles, the primary amine
protons were observed in the region of 6.10–6.58 ppm and in several cases
the assignment were confirmed by D2O exchange. The proton of the imida-
zole ring (H-2) appeared as a sharp singlet in the range of 7.41–7.50 ppm.
The 13C NMR spectra of the compounds (2a–2d) had the expected number
of peaks. The C-2 carbon of the imidazole ring appeared in the region of
136.7–137.7 ppm.
EXPERIMENTAL
1
The H NMR spectra were recorded on Hitachi-Perkin-Elmer R24B
(60 MHz) or Bruker XL 300 (300 MHz) instruments (with J-values given in
hertz), 13C NMR spectra (with DEPT 135) either on a Bruker WP80 or
XL300 instrument, and IR spectra on a Shimadzu IR-435 spectrophot-
ometer. Mass spectra were recorded on a Kratos Concept instrument. The
melting points were measured on an Electrothermal digital melting point
apparatus and are uncorrected.
General procedure for the preparation of the 5-Amino-1-aryl-4-cyanoi-
midazoles (3a–3d). A suspension of the corresponding aryl-(Z)-N-[2-amino-
1,2-dicyanovinyl]formamidine (2a–2d) (1.00 g) in potassium hydroxide
solution (1 M, 10 cm3) was stirred at room temperature until TLC showed
complete consumption of the starting material. The precipitated product
was filtered off, washed with water (5 cm3), followed by a mixture of dry
diethyl ether/ethanol (10 : 1) and air-dried in the absence of light to give the
desired products (3a–3d).

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YAHYA-ZADEH AND BOOTH
5-Amino-1-(2-chlorobenzyl)-4-cyanoimidazole (3a): Recrystallisation of
the product from dry diethyl ether/ethanol (1 : 1) and air-dried in the
absence of light to give white crystals of (3a) (0.76 g, 3.28 mmol, 85%).
m.p. 112–114ꢁC (decomp.). [Found: C, 56.3; H, 4.0; N, 23.8; Cl, 14.8.
C11H9N4Cl requires C, 56.8; H, 3.87; N, 24.1; Cl, 1.52%]; m/z (FAB) 233
(M þ 1)þ 100%, 232 (M)þ 34%, 192 [(MÀ1)-CN2H2]þ 34%, 154 [(MÀ1)-
C3H2N3]þ 6.7%, 136 (32%), 125 (54%); dH (300 MHz, d6-DMSO) 5.42 (s,
2H, CH2), 6.58 (s, 2H, NH2), 7.07 (dd, 1H,3 J12,13 7 Hz, 4J11,13 1.5 Hz, H13),
7.42 (s, 1H, H2), 7.63–7.68 (overlapping 2 ꢂ dt, 2H, 4J11,13 2 Hz, 3J11,10 8 Hz,
3
4
H11 and H12), 7.85 (dd, 1H, J10,11 7 Hz, J10,12 1.5 Hz, H10) ppm:
dC (75 MHz, d6-DMSO) 48.1 (C7, by DEPT 135), 94.2 (C4), 121.3 (C6),
131.5 (C12), 133.3 (C13), 133.4 (C11), 135.7 (C10), 136.8 (C9), 137.7 (C2),
139.6 (C8), 151.9 (C5) ppm; nmax (Nujol mull) 3440m, 3380s, 3330s, 3200s,
(N-H str.), 2220s, (CH str.), 1655s (C¼N str.), 1580s (N-H bend), 1530s,
1480s, 1440s, 1360s, 1280s, 1210s, 1065s, 1060s, 980s, 860m, 820m, 780s,
740m, 710m cm1.
5-Amino-1-(3,4-dimethoxybenzyl)-4-cyanoimidazole (3b): Recrystalli-
sation of the product from ethanol/methanol (1 : 1) give pale yellow crystals
of (3b) (0.80 g, 3.13 mmol, 90%). m.p. 171–172.5ꢁC (decomp.). [Found: C,
60.7; H, 5.3; N, 21.4. C13H14N4O2 requires C, 60.5; H, 5.4; N, 21.7%]; m/z
(Cl, NH3) 259 (M þ 1)þ 21.4%, 153 (M-C4H3N4)À 100%; dH (300 MHz,
d6-DMSO) 3.88 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, H7),
4
6.42 (s, 2H, NH2), 6.90 (dd, 1H,3 J9,10 8 Hz, J9,13 2 Hz, H9), 7.08 (d, 1H,
4
3J10,9 8 Hz, H10), 7.14 (d, 1H, J13,9 2 Hz, H13), 7.42 (s, 1H, H2) ppm:
dC (75 MHz, d6-DMSO) 50.0 (C7, by DEPT 135), 59.5 (C14 and C15 over-
lapping), 94.3 (C4), 115.7 and 115.9 (C10 and C13), 121.6 (C6), 123.9 (C9),
132.6 (C8), 136.7 (C2), 151.6 (C5), 152.5 and 152.8 (C11 and C12) ppm; nmax
(Nujol mull) 3400s, 3395m, 3220s, 3160s, 3120w (N-H str.), 2210s, 2200s
(CN str.), 1655s (C¼N str.), 1610s (N-H bend), 1580s, 1525s, 1265s, 1165s,
1140s, 1025s, 865s, 820m, 780s, 740m cmÀ1
.

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5-AMINO-1-ARYL-4-CYANOIMIDAZOLES
3229
5-Amino-1-(3,4-dimethoxyphenyl)-4-cyanoimidazole (3c): Recrystallisa-
tion of the product from ethanol/methanol (1 : 1) gave pale yellow crystals of
(3c) (0.80 g, 3.28 mmol, 89%). m.p. 218–219ꢁC (decomp.). [Found: C, 59.2;
H, 4.6; N, 22.6. Calc. for C12H12N4O2 C, 59.0; H, 4.9; N, 22.9%]; m/z (Cl,
NH3) 245 (M þ 1)þ 100%, 137 (M-C4H3N4)þ 3%; dH (300 MHz, d6-DMSO)
3.96 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.30 (s, 2H, NH2), 7.14 (dd, 1H,
4
4
3
3J8,9 8 Hz, J8,12 2 Hz H8), 7.20 (d, 1H, J12,8 2 Hz, H12), 7.28 (d, 1H, J9,8
8 Hz, H9), 7.50 (s, 1H, H2) ppm; dC (75 MHz, d6-DMSO) 59.6 and 59.7
(C13 and C14), 94.3 (C4), 113.6 and 115.9 (C9 and C12), 121.1 (C6), 121.6
(C8), 130.4 (C7), 136.6 (C2), 151.4 (C5), 152.9 and 153.1 (C10 and C11)
ppm; nmax (Nujol mull) 3460s, 3385m, 3220s, 3140s, (N-H str.), 2220s, 2200s
(CN str.), 1650s (C¼N str.), 1615s (N-H bend), 1595s (N-H bend), 1525s,
1255s, 1160s, 1040s, 880s, 780s cmÀ1
.
5-Amino-1-(4-methoxybenzyl)-4-cyanoimidazole (3d): Recrystallisation
of the product from ethanol/methanol (1 : 1) gave white crystals of (3d)
(0.82 g, 3.83 mmol, 0.93%). m.p. 167–168ꢁC (decomp.). [Found: C, 61.4;
H, 4.7; N, 25.9. Calc. for C11H10N4O C, 61.7; H, 4.7; N, 26.2%]; m/z
(FAB) 214 (M)þ 100%; dH (300 MHz, d6-DMSO) 3.81 (s, 3H, OCH3),
3
6.10 (s, 2H, NH2), 7.15 (d, 2H, J9,8 9 Hz, H9 and H11), 7.39 (d, 2H,

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YAHYA-ZADEH AND BOOTH
3J12,11 9 Hz, H8 and H12), 7.41 (s, 1H, H2) ppm; dC (75 MHz, d6-DMSO)
59.6 (C13), 94.7 (C4), 119.1 (C9 and C11), 121.1 (C6), 130.5 (C7), 131.1 (C8
and C12), 136.8 (C2), 151.6 (C5), 163.4 (C10) ppm; nmax (Nujol mull)
3380m, 3340s, 3200s, 3180m, (N-H str.), 2240s, 2200s (CN str.), 1655s
(C¼N str.), 1595s (N-H bend), 1530s, 1270s, 1040s, 970s, 860s, 815s cmÀ1
.
REFERENCES
1. Sen, A.K.; Mukhopadhyay, A.K. Ind. J. Chem. 1984, 23B, 870.
2. Frank, I.; Zeller, M. Synth. Commun. 1990, 20, 2519.
3. Booth, B.L.; Alves, M.J.; Proenca, M.F.J.R.P. J. Chem. Soc. Perkin
Trans. 1, 1992, 913.
4. Alves, M.J.; Booth, B.L.; Al-Duaij, O.Kh.; Eastwood, P.R.; Nezhat, L.;
Proenca, M.F.J.R.P.; Ramos, A.S. J. Chem. Research (S) 1993, 402; J.
Chem. Research (M), 1993, 2701.
5. Booth, B.L.; Alves, M.J.; Carvalho, A.; Eastwood, P.R.; Nezhat, L.
J. Chem. Soc. Perkin Trans. 2, 1994, 1949.
6. Booth, B.L.; Alves, M.J.; Proenca, M.F.J.R.P. J. Chem. Soc. Perkin
Trans. 1, 1990, 1705.
7. Alves, M.J.; Al-Duaij, O.Kh.; Booth, B.L.; Carvalho, A.; Eastwood,
P.R.; Proenca, M.F.J.R.P. J. Chem. Soc. Perkin Trans. 1 1990, 1705.
8. Woodward, D.W. U.S. Patent 2 534 331/1950.
Received in the UK November 6, 2000

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