Jan-Feb 2007 A Facile Regioselective Synthesis of (5-Amino-4-cyano-1H-imidazol-1-yl) Benzoic Acids
17
Hz), 8.22 (s, 1 H, CH), 9.20 (br s, 1 H, 2-H) ppm. NH was not
shown on the spectrum. 13C nmr (acetone-d6/ DMSO-d6 50:3): ꢀ
106.0 (C-2), 114.3 (CN), 115.6 (CN), 121.2 (C-1), 121.9 (Ar),
125.6 (Ar), 127.7 (Ar), 130.3 (Ar), 131.4 (Ar), 136.8 (Ar), 148.5
(HC=N), 167.4 (CO) ppm.
1701, 1644, 1603, 1583 cm-1. 1H nmr (DMSO-d6): ꢀ 3.80 (s, 3 H,
OCH3), 6.60 (s, 2 H, NH2), 7.70 (br s, 2 H, 3-H and 5-H), 7.90
(d, 2 H, 2-H and 6-H, J = 9.0 Hz), 8.00 (br s, 1 H, CH), 10.30 (s,
1 H, NH) ppm. 13C nmr (DMSO-d6): ꢀ 51.8 (OCH3), 104.2 (C-2),
114.7 (CN), 115.5 (CN), 117.7 (Ar), 120.1 (C-1), 123.3 (Ar),
130.6 (Ar), 143.6 (Ar), 147.1 (HC=N), 168.8 (CO) ppm. ms (CI
CH4): m/z (%) 270 (M++1, 20), 269 (M+, 42). Anal. Calcd for
C13H11N5O2: C, 58.0; H, 4.10; N, 26.0. Found: C, 57.88; H, 4.33;
N, 25.66.
The mother liquor was concentrated in the rotary evaporator (bath
temperature 35 ºC) leading to a yellow solid, which was collected by
filtration and washed with dichloromethane. The product was
identified as diaminomaleonitrile, 0.21 g (32%) by comparison of its
IR spectrum with that of an authentic sample [23a].
General Procedure for Preparation of the 3-(5-Amino-4-
cyano-1H-imidazol-1-yl) benzoic acids 3. Formamidine (2)
(5.85 mmol) was added to a saturated solution of sodium
hydroxide in ethanol/water 1:0.01 (38.9 mL) and the mixture
was stirred at room temperature for 1-2.5 hours (Scheme 1).
The reaction was monitored by TLC (chloroformꢁethanol
7.5:2.5). Diethyl ether was added and the precipitate was
collected by filtration, washed with the same solvent and dried
under vacuum (25 ºC) to give the required imidazole 3.
3-{[(Z)-2-Amino-1,2-dicyanovinyl]amino}methyleneamino-
4-methoxybenzoic acid (2d). Reaction of 1 with 3-amino-4-
methoxybenzoic acid gave the amidine 2d as a pinkish solid,
0.73 g (42%), mp 243.1-245.7 ºC; Rf 0.60 (chloroformꢁethanol
8:2). ir (KBr 1%): ꢂ 3460, 3314, 2942, 2227 (CN), 2205 (CN),
1701 (CO), 1639, 1600, 1545, 1490, 1446 cm-1. 1H nmr
(acetone-d6/ DMSO-d6 50:3) isomers A and B in 70:30 ratio: ꢀ
3.97 (s, 3 H, OCH3 B), 4.04 (s, 3 H, OCH3 A), 6.0 (s, 2 H, NH2 A
and B), 7.11 (d,1 H, 5-H B, J = 8.4 Hz), 7.16 (d,1 H, 5-H A, J =
8.4 Hz), 7.73 (dd,1 H, 6-H B, J = 8.4 and 2.0 Hz), 7.76 (dd, 1 H,
6-H A, J = 8.4 and 2.0 Hz), 8.20 (br s, 1 H, CH, A and B), 9.20
(br s, 1 H, 2-H A and B) ppm. NH was not showed on the
spectrum. 13C nmr (acetone-d6/ DMSO-d6 50:3): ꢀ 55.7 (OCH3),
106.0 (C-2), 109.1 (Ar), 109.9 (Ar), 113.5 (CN), 114.9 (CN),
123.2 (Ar), 125.4 (Ar), 147.5 (HC=N), 151.9 (Ar), 167.0 (CO)
ppm. The assignments were supported by the Dept 45 technique.
ms (EI): m/z (%) 285 (M+, 8).
3-{[(Z)-2-Amino-1,2-dicyanovinyl]amino}methylene-
amino-4-hydroxybenzoic acid (2e). Reaction of 1 with 3-
amino-4-hydroxybenzoic acid gave the amidine 2e as a pink
solid, 1.34 g (81%), it did not melt until 313 ºC; Rf 0.45
(chloroformꢁethanol 8:2). ir (KBr 1%): ꢂ 3334, 2233 (CN),
3-(5-Amino-4-cyano-1H-imidazol-1-yl) benzoic acid (3a).
The product of cyclisation of 2a was obtained as a brown solid,
1.33 g (77 %), mp above 322 ºC; Rf 0.61 (chloroformꢁethanol
2.5:7.5). ir (KBr 1%): ꢂ 3407, 2212, 1678, 1654, 1560, 1519
1
cm-1. H nmr (DMSO-d6): ꢀ 6.10 (br s, 2 H, NH2), 7.32-7.36 (m,
1
2210 (CN), 1677 (CO), 1637, 1602, 1550, 1458 cm-1. H nmr
1 H, 6 or 4-H), 7.37 (s, 1 H, C-H), 7.44 (t, 1 H, 5-H, J = 7.5 Hz),
7.81 (t, 1 H, 2-H, J = 1.8 Hz), 7.90-7.96 (m, 1 H, 4 or 6-H). 13C
nmr (DMSO-d6): ꢀ 90.0 (C-4), 117.2 (CN), 125.4 (Ar), 125.6
(Ar), 128.6 (Ar), 129.2 (Ar), 132.6 (C-2), 133.0 (Ar), 142.8 (Ar),
147.4 (C-5), 168.0 (CO). hrms: calcd. for C11H8N4O2 [M+]
228.0647; found 228.0646.
(acetone- d6/ DMSO-d6 50:3) ꢀ 7.02 (d, 1 H, 5-H, J = 8.1 Hz),
7.63 (dd, 1 H, 6-H, J = 8.1 and 2.1 Hz), 8.24 (br s, 1 H, CH),
8.90-9.40 (br s, <2H, 2-H) ppm. NH2 and NH were not shown
on the spectrum. 13C nmr (acetone-d6/ DMSO-d6 50:3): ꢀ 109.1
(Ar), 109.9 (Ar), 114.9 (CN), 113.5 (CN), 123.2 (Ar), 125.4
(Ar), 151.9 (Ar), 147.5 (HC=N), 167.0 (CO) ppm.
3-(5-Amino-4-cyano-1H-imidazol-1-yl)-4-methylbenzoic
acid (3b). The product of cyclisation of 3b was obtained as an
off-white solid 1.42 g (100%), mp above 322 ºC; Rf 0.56
(chloroformꢁethanol 2.5:7.5). ir (KBr 1%): ꢂ 3309, 3178, 2209,
Ethyl 3-{[(Z)-2-amino-1,2-dicyanovinyl]amino}methyl-
eneaminobenzoate (5a). Ethyl 3-aminobenzoate (1.0 g, 6.06
mmol) and anilinium chloride (catalytic amount) were added
to a suspension of 2-amino-1,2-dicyanovinylformimidate (1)
(1.0 g, 6.1 mmol) in ethanol (7 mL) while the mixture was
stirred in an ice bath (0-5 ºC). The mixture was kept stirring
at low temperature for 27 hours. The reaction was monitored
by TLC (chloroformꢁethanol 9:1). The precipitate was
collected by filtration, washed with diethyl ether and dried
under vacuum (25 ºC) in the dark to give amidine 5a as an
off-white solid, 1.38 g (80%); Rf 0.54 (chloroformꢁethanol
9:1). ir (KBr 1%): ꢂ 3449, 3332, 2222, 2202, 1711, 1639,
1
1654, 1599, 1578, 1552, 1516, 1451 cm-1. H nmr (DMSO-d6)
isomers A and B in 70:30 ratio: ꢀ 2.04 (s, 3 H, CH3 A), 2.25 (s,
3 H, CH3 B) 6.0 (br s, 2 H, NH2 A and B), 7.05 (d, 1 H, 5-H B, J
= 8.0 Hz), 7.23 (s, 1 H, C-H, A), 7.32 (d, 1 H, 5-H A, J = 8.0
Hz), 7.48 (dd, 1 H, 6-H B, J = 8.0 Hz and 1.5 Hz), 7.65 (d, 1 H,
2-H A, J = 1.5 Hz), 7.60-7.90 (br s, 1 H, C-H B), 7.89 (dd, 1 H,
6-H A, J = 8.0 Hz and 1.5 Hz), 7.94 (d, 1 H, 2-H B, J = 1.5 Hz,)
ppm. 13C nmr (DMSO-d6): ꢀ 18.2 (OCH3), 98.8 (C-4), 117.0
(CN), 128.3 (Ar), 129.9 (Ar), 130.2 (Ar), 131.3 (Ar), 132.5 (C-
2), 135.2 (Ar), 141.1 (Ar), 147.9 (C-5), 167.2 (CO) ppm. hrms:
calcd. for C12H10N4O2 [M+] 242.0804; found 242.0808.
1
1611, 1560, 1492 cm-1. H nmr (DMSO-d6): ꢀ 1.3 (t, 3 H,
CH3, J = 7.3 Hz), 4.32 (q, 2 H, CH2, J = 7.3 Hz), 6.45 (s, 2
H, NH2), 7.48 (t, 1 H, 5-H, J = 7.5 Hz), 7.62 (d, 1 H, 4-H or
6-H, J = 7.5 Hz), 7.90-8.20 (m, 3 H, C-H, 2-H and 6-H or 2-
H and 4-H), 10.20 (br d, 1 H, J = 4.4 Hz, N-H) ppm. ms (EI):
m/z (%) 283 (M+, 49).
Methyl 4-{[(Z)-2-amino-1,2-dicyanovinyl]amino}methylene-
aminobenzoate (5b). 2-Amino-1,2-dicyanovinylformimidate 1
(1.01 g, 6.16 mmol) was added to a suspension of 4-
methylaminobenzoate (0.93 g, 6.16 mmol) in methanol (10 ml).
A catalytic amount of anilinium chloride was added to the
reaction mixture that was stirred at 23 ºC for 20 hours. The solid
suspension was filtered and washed with methanol leading to a
lemon-yellow solid identified as compound 5b, 1.12 g (68%),
mp 180.0-181.0 ºC (dec). ir (oil): ꢂ 3456, 3310, 2223, 2203,
3-(5-Amino-4-cyano-1H-imidazol-1-yl)-4-chlorobenzoic
acid (3c). The product of cyclisation of 2c was obtained as a
pinkish solid, (1.54 g, 99%), mp above 320 ºC, Rf 0.59
(chloroformꢁethanol 2.5:7.5). ir (KBr 1%): ꢂ 3396, 2215, 1647,
1
1611, 1589, 1560, 1516, 1417 cm-1. H nmr (DMSO-d6): ꢀ 6.18
(br s, 2 H, NH2), 7.29 (s, 1 H, C-H), 7.58 (d, 1 H, 5-H, J = 8.4
Hz,), 7.81 (d, 1 H, 2-H, J = 1.8 Hz), 7.97 (dd, 1 H, 6-H, J = 8.4
and 1.8 Hz) ppm. 13C nmr (DMSO-d6): ꢀ 89.5 (C-4), 117.2 (CN),
129.1 (Ar), 129.8 (Ar), 130.2 (Ar), 131.3 (Ar), 132.3 (Ar), 132.3
(C-2), 141.8 (Ar), 148.2 (C-5), 166.6 (CO) ppm. hrms: calcd. for
C11H7N4O235Cl [M+] 262.0258; found 262.0261, calcd. for
C11H7N4O237Cl [M+] 264.0228; found 264.0234.