Polyfunctional imidazoles: VI.* synthesis of 2-amino-1-aryl-4-chloro- 1-imidazole-5-carboxylic acids derivatives

Article abstract of DOI:10.1134/S1070428012050132

Aryl-2,4-dichloro-5-formylimidazoles by a successive treatment with hydroxylamine and thionyl chloride were converted into 1-aryl-2,4- dichloroimidazole-5-carbonitriles which by the action of sodium azide and tin(II) chloride were transformed into 2-amino-1-aryl-4-chloroimidazole-5- carbonitriles. The consecutive reactions of 2-azido-1-aryl-4-chloro-5- formylimidazoles with N-bromosuccinimide, methanol, or amides led to the formation of methyl esters and amides of 2-azido-1-aryl-4-chloroimidazole-5- carboxylic acids. The reduction of the latter with tin(II) chloride resulted in the corresponding derivatives of 2-amino-1-aryl-4-chloroimidazole-5-carboxylic acids, and the reduction of 2-azido-1-aryl-4-chloroimidazole-5-carboxylic acids was accompanied with decarboxylation and yielded 2-amino-1-aryl-4- chloroimidazoles.

Full text of DOI:10.1134/S1070428012050132

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 5, pp. 705−710. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.A. Chornous, A.N. Grozav, M.V. Vovk, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 5, pp. 707−713.
Polyfunctional Imidazoles: VI.* Synthesis
of 2-Amino-1-aryl-4-chloro-1Н-imidazole-5-carboxylic
Acids Derivatives
V. A. Chornousa, A. N. Grozava, and M. V. Vovkb
aBukovinian State Medical University, Chernovtsi, 58000 Ukraine
e-mail: chornous@inbox.ru
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094 Ukraine
e-mail: mvovk@i.com.ua
Received October 31, 2011
Abstract—Aryl-2,4-dichloro-5-formylimidazoles by a successive treatment with hydroxylamine and thionyl
chloride were converted into 1-aryl-2,4-dichloroimidazole-5-carbonitriles which by the action of sodium azide
and tin(II) chloride were transformed into 2-amino-1-aryl-4-chloroimidazole-5-carbonitriles. The consecutive
reactions of 2-azido-1-aryl-4-chloro-5-formylimidazoles with N-bromosuccinimide, methanol, or amides led to
the formation of methyl esters and amides of 2-azido-1-aryl-4-chloroimidazole-5-carboxylic acids. The reduction
of the latter with tin(II) chloride resulted in the corresponding derivatives of 2-amino-1-aryl-4-chloroimidazole-
5-carboxylic acids, and the reduction of 2-azido-1-aryl-4-chloroimidazole-5-carboxylic acids was accompanied
with decarboxylation and yielded 2-amino-1-aryl-4-chloroimidazoles.
DOI: 10.1134/S1070428012050132
2-Aminoimidazoles are widely used in the synthesis
of compounds with a pronounced biological action [2–4].
Besides the structural fragment of 2-aminoimidazole is
present in the composition of some alkaloids isolated
from sea animals [5–7].
ficient procedures for the synthesis of 2-aminoimidazoles
containing in the position 4 a chlorine atom, and the
position 5 a nitrile, carboxy, ester , or amido group. The
introduction into the imidazole ring of a chlorine atom
supplies it with fungicidal properties[16, 17], and of
a cyano group results in the fungicidal [18] and herbicidal
[19] activity. The ester group turned out to be very useful
for the chemical modification of the imidazole ring [2, 4].
Two approaches are commonly used in the synthesis
of 2-aminoimidazole and its derivatives. The first one
includes the formation of the imidazole ring with the
simultaneous introduction of the amine function and con-
sists in the condensation of α-aminocarbonyl compounds
with cyanamide [8–10], α-diketones with guanidine [11].
or α-haloketones with N-acetylguanidine [12]. The second
approach involves the introduction of the amine function
into the position 2 of the imidazole ring by (а) coupling
with aryldiazonium salts followed by reduction [13], (b)
metallation with subsequent treatment with arylazides and
acids [14], (c) exchange reaction of 2-chloroimidazoles
with N,N-dialkylamines [15]. Yet the mentioned transfor-
mations are unsuitable for the preparation of imidazole
derivatives with a free amino group in the position 2.
For the purposeful introduction of the amino group we
chose the recently synthesized [15] 1-aryl-2,4-dichloro-
5-formylimidazoles Iа–Ie which were turned with the
use of hydroxylamine into oximes IIа–IIe and further
by treating with thionyl chloride were converted into
nitriles IIIа–IIIe. The direct replacement of the chlorine
atom in the position 2 of compounds III by heating with
alcoholic ammonia failed, and therefore we used the in-
troduction of an azido group in the mentioned position.
2,4-Dichloro-5-cyanoimidazoles IIIа–IIIe under mild
conditions (DMF, 20°С) cleanly reacted with sodium
azide giving 2-azido-substituted derivatives IVа–IVe
whose reduction with tin(II) chloride (procedure а) or
with potassium hydrogen sulfide (procedure b) afforded
2-amino-4-chloroimidazole-5-carbonitriles Vа–Ve.
Therefore we regarded as useful the development of ef-
_______________
* For Communication V, see [1].
705

CHORNOUS et al.
706
Cl
N
Cl
CN
Cl
N
N
SOCl2
H2NOH
Cl
CH NOH
Cl
Cl
N
N
N
O
Ar
Ar
Ar
IIа_IIe
IIIа_IIIe
Iа_Ie
Cl
CN
Cl
CN
(a) SnCl2
(b) KSH
NaN3
N
N
H2N
N3
N
N
Ar
Ar
Vа_Ve
IVа_IVe
Ar = Ph (a), 4-FC6H4 (b), 4-BrC6H4 (c), 4-MeC6H4 (d), 4-MeOC6H4 (e).
The structure of aminonitriles Vа–Ve is in agreement
with their spectral characteristics. The IR spectra contain
the absorption bands of the С≡N (2215–2225 cm–1) and
NН2 (3415–3430 cm–1) groups. In the 1Н NMR spectra
the signal of the amino group is observed in the range
6.64–6.72 ppm The characteristic signals in the 13С
NMR spectra are the singlets of the carbon atoms of the
imidazole ring: 95–96 (С5), 132–139 (С2), 147–151ppm
(С4) and of С≡N group (109–111ppm).
chloro-imidazole-5-carboxylic acids was performed with
the use of 2-azido-4-chloro-5-formylimidazoles VIа–VIe
[15]. Their bromination with N-bromosuccinimide fol-
lowed by the treatment of the obtained acyl bromides
with methanol (VIIа) or amines (VIIb–VIIe) furnished
esters VIIIа–VIIIe and amides VIIIf–VIIIi of 2-azido-
4-chloroimidazole-5-carboxylic acids. The latter by the
reaction with tin(II) chloride were mildly reduced into
derivatives of 2-amino-4-chloro-imidazole-5-carboxylic
acids IХа–IXi.
The synthesis of esters and amides of 2-amino-4-
(1) NBS
(2) HX
VIIа_VIIe
Cl
Cl
Cl
N
N
N
SnCl2
X
X
N3
H2N
N3
N
N
N
O
O
O
Ar
VIIIа_VIIIi
Ar
IXа_IXi
Ar
VIа_VIe
VI, Аr = Рh (а), 4-FС6Н4 (b), 4-СlС6Н4 (c), 4-ВrС6Н4 (d), 4-MеС6Н4(e); VII, Х = MеО (а), PhCH2NH (b), 4-MeC6H4NH (c), 3-FC6H4NH
(d), (CH2)5N (e); VIII, IХ, Х = MeO, Ar = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 4-BrC6H4 (d), 4-MеС6Н4 (e); X = PhCH2NH, Ar =Ph (f);
X = 4-MeC6H4NH, Ar = 4-ClC6H4 (g); X = 3-FC6H4NH, Ar = 4-MeC6H4 (h); X = (CH2)5N, Ar = 4-BrC6H4 (i).
Formerly [20] the alkaline hydrolysis of esters of
2-amino-4-cyanoimidazole-5-carboxylic acids made it
possible to obtain the proper acids that are prone to de-
carboxylation at the temperature over 200°С. Our attempt
to hydrolyze esters IXa, IXb with lithium hydroxide
under mild conditions was unsuccessful. In the formed
complex mixture of compounds no corresponding ac-
ids were detected. We tried to synthesize them from
azidoaldehydes VIa, VIc, VIe, VIf by first oxidation of
the aldehyde group and further reduction of the azido
group. The oxidation of these aldehydes with potassium
permanganate was an ambiguous process, and azidoacids
Xа–Xd were isolated only in 20–25% yield.At the reduc-
tion of the latter products with tin(II) chloride under mild
Cl
Cl
N
N
KMnO4
SnCl2
_CO2
OH
VIа, VIc, VIe, VIf
N3
H2N
N
N
O
Ar
Xа_Xd
Ar
XIа_XId
VI, Ar = 4-MеОС6Н4 (f); Х, ХІ, Аr = Ph (a), 4-СlС6Н4 (b), 4-MеС6Н4 (c), 4-MеОС6Н4 (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

POLYFUNCTIONAL IMIDAZOLES: VI.
707
conditions alongside the reduction of the azido group
decarboxylation occurred giving previously unknown
4-chloroimidazol-2-amines XIа–XId whose Н NMR
7.64 s (1Н, СН=), 11.81 s (1Н, ОН). Found, %: C 48.77;
H 3.42; N 15.65. С11H9Cl2N3O. Calculated, %: C 48.91;
H 3.36; N 15.56.
1
spectra besides the singlets of the protons of NH2 group
(5.58–5.63 ppm) contained the singlets of the protons Н5
of the imidazole ring at 6.82–6.91 ppm.
1-(4-Methoxyphenyl)-2,4-dichloro-1Н-imidazole-
5-carbaldehyde oxime (IIe). Yield 86%, mp 155–157°С.
1
IR spectrum, cm–1: 3405 (OH), 1620 (С=N). Н NMR
spectrum, δ, ppm: 3.84 s (3Н, СН3О), 7.11 d (2Нarom
,
EXPERIMENTAL
J 8.5 Hz), 7.43 d (2Нarom, J 8.5 Hz), 7.63 s (1Н, СН=),
11.59 s (1Н, ОН). Found, %: C 46.07; H 3.22; N 14.55.
С11H9Cl2N3O2. Calculated, %: C 46.18; H 3.17; N 14.69.
IR spectra were recorded on a spectrophotometer UR-
20 from pellets with KBr (compound IXf from solution
in СН2Сl2). Н and 13С NMR spectra were registered
on a spectrometer Bruker Avance DRX-500 (500.13,
125.75 MHz respectively) from solutions in DMSO-d6,
internal reference TMS. GC-MS measurements were
carried out on an instrument Aligent 1100/DAD/HSD/
VLG119562.
Nitriles IIIа–IIIe. To a slurry of 0.03 mol of oxime
IIа–IIe in 60 ml of toluene was added 3.9 g (0.033 mol)
of thionyl chloride, and the mixture was boiled for 3 h.
The solvent was evaporated, the residue was washed
with water, filtered off, dried, and crystallized from 80%
aqueous ethanol.
1
1-Phenyl-2,4-dichloro-1Н-imidazole-5-carbonitrile
(IIIа). Yield 80%, mp 63–64°С. IR spectrum, cm–1: 2220
(С≡N). 1Н NMR spectrum, δ, ppm: 7.59–7.68 m (5Нarom).
Found, %: C 50.12; H 2.22; N 17.53. С10H5Cl2N3.
Calculated, %: C 50.45; H 2.12; N 17.65.
Oximes IIа–IIe. To a solution of 0.05 mol of alde-
hyde Iа–Ie in 20 ml of ethanol was added a solution of
3.5 g (0.05 mol) of hydroxylamine hydrochloride and
6.8 g (0.05 mol) of sodium acetate trihydrate in 25 ml of
water, the mixture was heated to boiling and diluted with
150 ml of water. The separated precipitate was filtered
off, washed with water, and dried.
1-(4-Fluorophenyl)-2,4-dichloro-1Н-imidazole-
5-carbonitrile (IIIb). Yield 70%, mp 99–100°С. IR
spectrum, cm–1: 2220 (С≡N). 1Н NMR spectrum, δ, ppm:
7.54 t (2Нarom, J 8.2 Hz), 7.79–7.84 m (2Нarom). Found,
%: C 46.77; H 1.42; N 16.55. С10H4Cl2FN3. Calculated,
%: C 46.91; H 1.57; N 16.41.
1-Phenyl-2,4-dichloro-1Н-imidazole-5-carb-
aldehyde oxime (IIа). Yield 90%, mp 153–154°С. IR
spectrum, cm–1: 3410 (OH), 1625 (C=N). 1Н NMR spec-
trum, δ, ppm: 7.51–7.60 m (5Нarom), 7.63 s (1Н, СН=),
11.52 s (1Н, ОН). Found, %: C 46.67; H 2.82; N 16.55.
С10H7Cl2N3O. Calculated, %: C 46.90; H 2.76; N 16.41.
1-(4-Bromophenyl)-2,4-dichloro-1Н-imidazole-
5-carbonitrile (IIIc). Yield 68%, mp 84–85°С. IR
spectrum, cm–1: 2225 (С≡N). 1Н NMR spectrum, δ, ppm:
7.71 d (2Нarom, J 8.4 Hz), 7.90 d (2Нarom, J 8.4 Hz). Found,
%: C 37.98; H 1.42; N 13.45. С10H4ВrCl2N3. Calculated,
%: C 37.89; H 1.27; N 13.26.
1-(4-Fluorophenyl)-2,4-dichloro-1Н-imidazole-5-
carbaldehyde oxime (IIb). Yield 82%, mp 178–180°С.
IR spectrum, cm–1: 3400 (OH), 1630 (С=N). Н NMR
spectrum, δ, ppm: 7.41–7.63 m (4Нarom), 7.70 s (1H,
CH=), 11.82 s (1Н, ОН). Found, %: C 43.57; H 2.32;
N 15.45. С10H6Cl2FN3O. Calculated, %: C 43.82; H 2.21;
N 15.33.
1
1-(4-Methylphenyl)-2,4-dichloro-1Н-imidazole-5-
carbonitrile (IIId). Yield 78%, mp 75°С. IR spectrum,
cm–1: 2220 (С≡N). 1Н NMR spectrum, δ, ppm: 2.42 s (3Н,
СН3), 7.40 d (2Нarom, J 8.0 Hz), 7.46 d (2Нarom, J 8.0 Hz).
13C NMR spectrum, δ, ppm: 20.38 (СН3), 105.79 (C5),
109.06 (С≡N), 126.66, 129.77, 135.15, 137.10 (Carom),
130.25 (С2), 141.03 (С4). Found, %: C 52.58; H 2.72;
N 16.78. С11H7Cl2N3. Calculated, %: C 52.41; H 2.80;
N 16.67.
1-(4-Bromophenyl)-2,4-dichloro-1Н-imidazole-5-
carbaldehyde oxime (IIc). Yield 78%, mp 136–137°С.
IR spectrum, cm–1: 3415 (OH), 1625 (С=N). Н NMR
spectrum, δ, ppm: 7.51 d (2Нarom, J 7.2 Hz), 7.73 s (1H,
CH=), 7.78 d (2Нarom, J 7.2 Hz), 11.79 s (1Н, ОН).
Found, %: C 35.67; H 1.72; N 12.75. С10H6ВrCl2N3O.
Calculated, %: C 35.86; H 1.81; N 12.54.
1
1-(4-Methoxyphenyl)-2,4-dichloro-1Н-imidazole-
5-carbonitrile (IIIe). Yield 76%, mp 83°С. IR spectrum,
cm–1: 2220 (С≡N). 1Н NMR spectrum, δ, ppm: 3.86 s (3Н,
СН3О), 7.18 d (2Нarom, J 8.8 Hz), 7.62 d (2Нarom, J 8.8
Hz). 13C NMR spectrum, δ, ppm: 55.61 (СН3О), 106.04
(C5), 109.14 (C≡N), 114.95, 125.38, 128.83, 160.76
1-(4-Methylphenyl)-2,4-dichloro-1Н-imidazole-5-
carbaldehyde oxime (IId). Yield 85%, mp 145–146°С.
IR spectrum, cm–1: 3430 (OH), 1620 (С=N). Н NMR
1
spectrum, δ, ppm: 2.40 s (3Н, СН3), 7.39 br.s (4Нarom),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

CHORNOUS et al.
708
(Сarom), 135.43 (C2), 136.91 (C4). Found, %: C 49.17;
H 2.52; N 15.82. С11H7Cl2N3O. Calculated, %: C 49.28;
H 2.63; N 15.67.
Nitriles Vа–Ve. а. To a solution of 1.7 g (7.5 mmol)
of tin(II) chloride dihydrate in 10 ml of conc. НСl was
added 20 ml of ethanol, then at stirring and cooling
0.0075 mol of nitrile IVа–IVe was added by small por-
tions within 0.5 h. The reaction mixture was poured into
100 ml of water, the reaction product was extracted into
ethyl acetate (2 × 20 ml), the organic layer was dried with
anhydrous sodium sulfate, the solvent was evaporated,
and the residue was crystallized from ethanol.
Nitriles IVа–IVe. To a solution of 0.01 mol of nitrile
IIIа–IIIe in 10 ml of DMF was added 0.98 g (0.015 mol)
of sodium azide, and the mixture was stirred at room
temperature over 12 h. The reaction mixture was poured
into 50 ml of water, the precipitate was filtered off, dried,
and crystallized from ethanol.
2-Azido-1-phenyl-4-chloro-1Н-imidazole-5-
carbonitrile (IVа). Yield 79%, mp 79–80°С. IR
spectrum, cm–1: 2245 (С≡N), 2165 (N3). 1Н NMR spec-
trum, δ, ppm: 7.54–7.63 m (5Нarom). Found, %: C 49.23;
H 2.22; N 34.17. С10H5ClN6. Calculated, %: C 49.10;
H 2.06; N 34.35.
b. To a solution of 7.5 mmol of nitrile IVа–IVe in
20 ml of ethanol at 10–20°С was added dropwise within
2 h 1.44 g (0.02 mol) of potassium hydrogen sulfide in
50 ml of 80% aqueous ethanol. The reaction mixture
was poured into 100 ml of water, the precipitate was
filtered off, washed with water, dried, and crystallized
from ethanol.
2-Azido-1-(4-fluorophenyl)-4-chloro-1Н-imid-
azole-5-carbonitrile (IVb). Yield 72%, mp 83–84°С.
2-Amino-1-phenyl-4-chloro-1Н-imidazole-5-
carbonitrile (Vа). Yield 69% (а), 74% (b), mp
151–152°С. IR spectrum, cm–1: 3415 (NH2), 2220
1
IR spectrum, cm–1: 2160 (N3), 2235 (С≡N). Н NMR
spectrum, δ, ppm: 7.59–7.84 m (4Нarom). 13C NMR spec-
trum, δ, ppm: 102.31 (C5), 109.61 (C≡N), 116.75 d (Сarom
,
1
(С≡N). Н NMR spectrum, δ, ppm: 6.78 s (2H, NH2),
2JС–F 25.2 Hz), 128.47, 128.97, 162.60 d (1JС–F 252.4 Hz)
(Сarom), 137.39 (C2), 143.23 (C4). Found, %: C 45.57;
H 1.42; N 32.15. С10H4ClFN6. Calculated, %: C 45.73;
H 1.54; N 32.00.
7.50–7.61 m (5Нarom). 13C NMR spectrum, δ, ppm: 96.17
(C5), 111.52 (С≡N), 126.59, 129.47, 129.98, 138.73
(Сarom), 133.22 (C2), 150.90 (C4). Found, %: C 54.78;
H 3.14; N 25.47. [M + 1]+ 219. С10H7ClN4. Calculated,
%: C 54.93; H 3.23; N 25.62. M 218.65
2-Azido-1-(4-bromophenyl)-4-chloro-1Н-imid-
azole-5-carbonitrile (IVc). Yield 70%, mp 116–117°С.
2-Amino-1-(4-fluorophenyl)-4-chloro-1Н-imid-
azole-5-carbonitrile (Vb). Yield 58% (а), 65% (b),
mp 159–160°С. IR spectrum, cm–1: 3430 (NH2), 2225
1
IR spectrum, cm–1: 2240 (С≡N), 2165 (N3). Н NMR
spectrum, δ, ppm: 7.59 d (2Нarom, J 8.8 Hz), 7.85 d
(2Нarom, J 8.8 Hz). Found, %: C 37.31; H 1.18; N 25.78.
С10H4ВrClN6. Calculated, %: C 37.12; H 1.25; N 25.98.
1
(С≡N). Н NMR spectrum, δ, ppm: 6.70 s (2H, NH2),
7.50–7.56 m (2Нarom), 7.81–7.88 m (2Нarom). 13C NMR
spectrum, δ, ppm: 95.98 (C5), 109.04 (С≡N), 117.00 d
2-Azido-1-(4-methylphenyl)-4-chloro-1Н-imid-
azole-5-carbonitrile (IVd). Yield 77%, mp 59–60°С. IR
spectrum, cm–1: 2165 (N3), 2240 (С≡N). 1Н NMR spec-
trum, δ, ppm: 2.40 s (3Н, СН3), 7.41 d (2Нarom, J 8.0 Hz),
(Сarom, 2JС–F 25.1 Hz), 129.13 (Сarom), 129.73 d (Сarom
2JС–F 8.7 Hz), 135.39 (C2), 147.17 (C4), 162.98 d (Сarom
,
,
1JС–F 251.5 Hz). Found, %: C 50.57; H 2.70; N 23.45.
[M + 1]+ 237. С10H6ClFN4. Calculated, %: C 50.76;
H 2.56; N 23.68. M 236.64.
13
7.48 d (2Нarom, J 8.0 Hz). C NMR spectrum, δ, ppm:
20.67 (СН3), 102.13 (C5), 109.66 (С≡N), 126.02, 129.68,
130.09, 140.32 (Сarom), 137.32 (C2), 143.18 (C4). Found,
%: C 50.98; H 2.62; N 32.68. С11H7ClN6. Calculated, %:
C 51.14; H 2.73; N 32.49.
2-Amino-1-(4-bromophenyl)-4-chloro-1Н-
imidazole-5-carbonitrile (Vc). Yield 57% (а), 55%
(b), mp 163–164°С. IR spectrum, cm–1: 3420 (NH2)
2220 (С≡N). 1Н NMR spectrum, δ, ppm: 6.75 br.s (1Н,
NH2), 7.49 d (2Нarom, J 8.8 Hz), 7.79 d (2Нarom, J 8.8 Hz).
13C NMR spectrum, δ, ppm: 96.12 (С5), 111.41 (С≡N),
122.76, 129.01, 132.97, 138.87 (Сarom), 132.49 (C2),
150.93 (C4). Found, %: C 40.15; H 1.88; N 18.61. [M +
1]+ 298. С10H6ВrClN4. Calculated, %: C 40.37; H 2.03;
N 18.83. M 297.54.
2-Azido-1-(4-methoxyphenyl)-4-chloro-1Н-
imidazole-5-carbonitrile (IVe). Yield 71%, mp
101–102°С. IR spectrum, cm–1: 2240 (С≡N), 2160 (N3).
1Н NMR spectrum, δ, ppm: 3.84 с (3Н, СН3О), 7.14 d
(2Нarom, J 8.4 Hz), 7.53 d (2Нarom, J 8.4 Hz). 13C NMR
spectrum, δ, ppm: 55.61 (СН3О), 102.43 (C5), 109.76
(С≡N), 114.78, 124.78, 127.82, 160.36 (Сarom), 135.05
(C2), 143.18 (C4). Found, %: C 47.87; H 2.42; N 30.79.
С11H7ClN6O. Calculated, %: C 48.10; H 2.57; N 30.60.
2-Amino-1-(4-methylphenyl)-4-chloro-1Н-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

POLYFUNCTIONAL IMIDAZOLES: VI.
709
1Н NMR spectrum, δ, ppm: 3.63 s (3Н, СН3О), 7.47 d
(2Нarom, J 8.8 Hz), 7.58 d (2Нarom, J 8.8 Hz). Found, %:
C 42.50; H 2.39; N 22.20. [M + 1]+ 312. С11H7Сl2N5O2.
Calculated, %: C 42.33; H 2.26; N 22.44. M 312.12.
imidazole-5-carbonitrile (Vd). Yield 62% (а), 69%
(b), mp 152–153°С. IR spectrum, cm–1: 3415 (NH2),
2215 (С≡N). Н NMR spectrum, δ, ppm: 2.40 с (3Н,
СН3), 6.72 с (2Н, NH2), 7.32–7.42 m (4Нarom). 13C
NMR spectrum, δ, ppm: 20.70 (СН3), 96.21 (С5), 111.58
(С≡N), 126.46, 130.43, 130.65, 138.50 (Сarom), 139.26
(C2), 150.99 (C4), Found, %: C 57.05; H 3.72; N 24.19.
[M + 1]+ 233.С11H9ClN4. Calculated, %: C 56.78; H 3.90;
N 24.08. M 232.67.
1
Methyl 2-azido-1-(4-bromophenyl)-4-chloro-
1Н-imidazole-5-carboxylate (VIIId). Yield 50%, mp
104–105°С. IR spectrum, cm–1: 2165 (N3), 1730 (С=О).
1Н NMR spectrum, δ, ppm: 3.64 s (3Н, СН3О), 7.40 d
(2Нarom, J 8.4Hz), 7.71 d (2Нarom, J 8.4 Hz). Found, %:
C 36.68; H 2.11; N 19.83. [M + 1]+ 357.С11H7BrСlN5O2.
Calculated, %: C 37.05; H 1.98; N 19.64. M 356.57.
2-Amino-1-(4-methoxyphenyl)-4-chloro-1Н-
imidazole-5-carbonitrile (Ve). Yield 60% (а), 63% (b),
mp 155–157°С. IR spectrum, cm–1: 3425 (NH2), 2220
(С≡N). 1Н NMR spectrum, δ, ppm: 3.84 s (3Н, СН3О),
Methyl 2-azido-1-(4-methylphenyl)-4-chloro-
1Н-imidazole-5-carboxylate (VIIIe). Yield 90%, mp
145–148°С. IR spectrum, cm–1: 2160 (N3), 1730 (С=О).
1Н NMR spectrum, δ, ppm: 2.37 s (3Н, СН3), 3.62 s (3Н,
СН3О), 7.29 br.s (4Нarom). Found, %: C 49.65; H 3.53;
N 24.09. [M + 1]+ 292. С12H10СlN5O2. Calculated, %:
C 49.41; H 3.46; N 24.01. M 291.70.
6.62 br.s (NH2), 7.12 d (2Нarom, J 8.4 Hz), 7.42 d (2Нarom
,
13
J 8.4 Hz). C NMR spectrum, δ, ppm: 55.53 (СН3О),
96.54 (C5), 111.60 (С≡N), 115.09, 125.75, 128.28, 159.84
(Сarom), 138.19 (C2), 151.22 (C4). Found, %: C 52.97;
H 3.48; N 22.72. [M + 1]+ 249.С11H9ClN4O. Calculated,
%: C 53.13; H 3.65; N 22.53. M 248.67.
Methyl 2-amino-1-aryl-4-chloro-1Н-imidazole-5-
carboxylates IXа–IXe. To a solution of 1.7 g (7.5 mmol)
of tin(II) chloride dihydrate in 10 ml of concn. HCl and
20 ml of ethanol was added and then at stirring and cool-
ing to 0–5°С was added within 0.5 h by small portions
7.5 mmol of ester VIIIа–VIIIe. The reaction mixture
was poured into в 100 ml of water, the reaction product
was extracted into ethyl acetate (2 × 20 ml), the organic
layer was dried with anhydrous sodium sulfate, the sol-
vent was evaporated, and the residue was crystallized
from methanol.
Methyl 2-azido-1-aryl-4-chloro-1Н-imidazole-5-
carboxylates VIIIа–VIIIe. To a solution of 0.01 mol
aldehyde VIа–VIe in 20 ml of tetrachloromethane was
added 2.67 g (0.015 mol) of N-bromosuccinimide, 0.01 g
of azobisisobutyronitrile, and the mixture was boiled for
2 h. The reaction mixture was cooled, the precipitate of
succinimide was filtered off, 1.6 g (0.05 mol) of methanol
was added to the filtrate, and the solution was boiled
for 1 h. The solvent was evaporated, the precipitate was
filtered off, washed with water, dried, and crystallized
from aqueous methanol.
Methyl 2-amino-1-phenyl-4-chloro-1Н-imidazole-
5-carboxylate (IXа). Yield 84%, mp 119–120°С. IR
Methyl 2-azido-1-phenyl-4-chloro-1Н-imidazole-
5-carboxylate (VIIIа). Yield 78%, mp 103–104°С.
1
spectrum, cm–1: 3390 (NH2), 1720 (С=О). Н NMR
1
IR spectrum, cm–1: 2160 (N3), 1730 (С=О). Н NMR
spectrum, δ, ppm: 3.51 s (3Н, СН3О), 6.22 s (2Н, NH2),
7.24–7.32 m (2Нarom), 7.44–7.50 m (3Нarom). 13C NMR
spectrum, δ, ppm: 50.61 (СН3О), 112.57 (С5), 127.57,
128.51, 129.12, 151.63 (Сarom), 135.59 (С2), 136.35 (С4),
158.24 (С=О). Found, %: C 52.23; H 4.06; N 16.67. [M +
1]+ 252. С11H10СlN3O2. Calculated, %: C 52.50; H 4.01;
N 16.70. M 251.67.
spectrum, δ, ppm: 3.65 s (3Н, СН3О), 7.41–7.52 m
(5Нarom). Found, %: C 47.81; H 2.72; N 25.40. [M +
1]+ 278. С11H8СlN5O2. Calculated, %: C 47.58; H 2.90;
N 25.22. M 277.67.
Methyl 2-azido-1-(4-fluorophenyl)-4-chloro-1Н-
imidazole-5-carboxylate (VIIIb). Yield 70%, mp
113–114°С. IR spectrum, cm–1: 1730 (С=О), 2165 (N3).
1Н NMR spectrum, δ, ppm: 3.62 s (3Н, СН3О), 7.32–
7.51 m (4Нarom). Found, %: C 44.41; H 2.42; N 23.63.
[M + 1]+ 296. С11H7СlFN5O2. Calculated, %: C 44.69;
H 2.39; N 23.69. M 295.66.
Methyl 2-amino-1-(4-fluorophenyl)-4-chloro-1Н-
imidazole-5-carboxylate (IXb). Yield 76%, mp 179–
180°С. IR spectrum, cm–1: 3400 (NH2), 1725 (С=О). 1Н
NMR spectrum, δ, ppm: 3.52 s (3Н, СН3О), 6.31 s (2Н,
NH2), 7.29–7.43 m (4Нarom). Found, %: C 48.72; H 3.43;
N 15.39. [M + 1]+ 270. С11H9СlFN3O2. Calculated, %:
C 49.00; H 3.36; N 15.58. M 269.66.
Methyl 2-azido-4-chloro-1-(4-chlorophenyl)-
1Н-imidazole-5-carboxylate (VIIIc). Yield 67%, mp
109–110°С. IR spectrum, cm–1: 2165 (N3), 1725 (С=О).
Methyl 2-amino-4-chloro-1-(4-chlorophenyl)--
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

CHORNOUS et al.
710
vent was evaporated. Amides IXf–IXi were purified by
reprecipitation in hexane from benzene or by crystalliza-
tion from ethanol.
imidazole-5-carboxylate (IXc). Yield 79%, mp 188–
189°С. IR spectrum, cm–1: 3385 (NH2), 1720 (С=О).
1Н NMR spectrum, δ, ppm: 3.53 s (3Н, СН3О), 6.36 s
(2Н, NH2), 7.35 d (2Нarom, J 8.4 Hz), 7.54 d (2Нarom
,
2-Amino-N-benzyl-1-phenyl-4-chloro-1Н-imid-
azole-5-carboxamide (IXf). Yield 63%, viscous oily
substance. IR spectrum, cm–1: 3380–3350 (NH), 1660
J 8.4 Hz). Found, %: C 46.41; H 3.06; N 14.52. [M+1]+
286. С11H9Сl2N3O2. Calculated, %: C 46.18; H 3.17;
N 14.69. M 286.12.
1
(С=О). Н NMR spectrum, δ, ppm: 4.32 d (2Н, СН2,
J 6.0 Hz), 5.92 s (2Н, NH2), 7.15–7.54 m (10Нarom),
8.94 t (1Н, NH, J 6.0 Hz). Found, %: C 62.76; H 4.39;
N 17.39. [M + 1]+ 327. С17H15ClN4O. Calculated, %:
C 62.48; H 4.63; N 17.14. M 326.79.
Methyl 2-amino-1-(4-bromophenyl)-4-chloro-
1Н-imidazole-5-carboxylate (IXd). Yield 64%, mp
181–182°С. IR spectrum, cm–1: 3395 (NH2), 1720 (С=О).
1Н NMR spectrum, δ, ppm: 3.50 s (3Н, СН3О), 6.31 s
2-Amino-N-(4-methylphenyl)-4-chloro-1-(4-
chlorophenyl)-1Н-imidazole-5-carboxamide (IXg).
Yield 58%, mp 125–126°С. IR spectrum, cm–1: 3345–
(2Н, NH2), 7.43 d (2Нarom, J 8.6 Hz), 7.75 d (2Нarom
,
J 8.6 Hz). Found, %: C 40.24; H 2.70; N 12.54. [M + 1]+
331. С11H9BrClN3O2. Calculated, %: C 39.97; H 2.74;
N 12.71. M 330.57.
1
3320 (NH), 1670 (С=О). Н NMR spectrum, δ, ppm:
2.28 s (3Н, СН3), 6.18 s (2Н, NH2), 7.38 d (2Н, СН2,
J 8.0 Hz), 7.56 d (2Н, СН2, J 8.0 Hz), 9.64 с (1Н, NH).
Found, %: C 56.30; H 3.73; N 15.28. [M + 1]+ 361.
С17H14Cl2N4O. Calculated, %: C 56.53; H 3.91; N 15.51.
M 361.23.
Methyl 2-amino-1-(4-methylphenyl)-4-chloro-
1Н-imidazole-5-carboxylate (IXe). Yield 80%, mp
156–157°С. IR spectrum, cm–1: 3405 (NH2), 1725
1
(С=О),. Н NMR spectrum, δ, ppm: 2.38 s (3Н, СН3),
3.52 s (3Н, СН3О), 6.21 s (2Н, NH2), 7.16 d (2Нarom
,
2-Amino-1-(4-methylphenyl)-N-(3-fluorophenyl)-
4-chloro-1Н-imidazole-5-carboxamide (IXh). Yield
65%, mp 199–200°С. IR spectrum, cm–1: 3350–
J 7.4 Hz), 7.33d (2Нarom, J 7.4 Hz). 13C NMR spectrum,
δ, ppm: 20.55 (СН3), 50.36 (СН3О), 112.59 (С5), 127.37,
129.71, 137.99, 151.69 (Сarom), 132.96 (С2), 136.45 (С4),
158.29 (С=О). Found, %: C 54.08; H 4.32; N 15.64. [M +
1]+ 266. С12H12ClN3O2. Calculated, %: C 54.25; H 4.55;
N 15.81. M 265.70.
1
3320 (NH), 1675 (С=О). Н NMR spectrum, δ, ppm:
2.35 s (3Н, СН3), 6.11 s (2Н, NH2), 7.17–7.42 m (8Нarom),
9.99 s (1Н, NH). Found, %: C 59.19; H 4.11; N 16.27.
[M + 1]+ 345. С17H14ClFN4O. Calculated, %: C 59.22;
H 4.09; N 16.25. M 344.78.
2-Amino-1-aryl-4-chloro-1Н-imidazole-5-
carboxamides IXf–IXi. To a solution of 0.01 mol of
aldehyde VIа, VIc–VIe in 20 ml of tetrachloromethane
was added 2.67 g (0.015 mol) of N-bromosuccinimide,
0.01 g of azobisisobutyronitrile, and the mixture was
boiled for 2 h. The reaction mixture was cooled to room
temperature, the precipitate of succinimide was filtered off
The filtrate was evaporated, to the residue was added 20 ml
of acetonitrile, 0.015 mol of amine VІIb–VIIe and 1.5 g
(0.015 mol) of triethylamine. The reaction mixture was
boiled for 1 h, the solvent was evaporated, to the residue
50 ml of water was added, the reaction product was ex-
tracted into ethyl acetate (2 × 20 ml), the organic layer
was dried with anhydrous sodium sulfate, the solvent was
evaporated. To the obtained oily residue of azidoamide
VІIIf–VIIIi was added at stirring and cooling within 0.5 h
1.7 g (0.02mol) of tin(II) chloride dihydrate in 10 ml of
concn. HCl and 20 ml of ethanol. The reaction mixture
was poured into в 100 ml of water, the reaction product
was extracted into ethyl acetate (2 × 20 ml), the organic
layer was dried with anhydrous sodium sulfate, the sol-
2-Amino-1-(4-bromophenyl)-4-chloro-1Н-
imidazol-5-yl(piperidin-1-yl)methanone (IXi). Yield
68%, mp 200–202°С. IR spectrum, cm–1: 3375 (NH),
1
1660 (С=О). Н NMR spectrum, δ, ppm: 1.41–1.56 m
(6Н, 3СН2), 3.38–3.42 m (4Н, 2СН2), 6.02 s (2Н,
NH2), 7.21 d (2Нarom, J 8.8 Hz), 7.68 (2Нarom, J 8.8 Hz).
Found, %: C 46.76; H 4.38; N 14.47. [M + 1]+ 384.
С15H16ВrСlN4O. Calculated, %: C 46.96; H 4.20;
N 14.60. M 383.68.
2-Azido-1-aryl-4-chloro-1Н-imidazole-5-carb-
oxylic acids Ха–Xd. To a solution of 0.01 mol of
aldehyde VІа, VIc,VIe, VIf in 20 ml of 80% aqueous
pyridine at stirring and cooling with water was added
4.74 g (0.03 mol) of potassium permanganate. The reac-
tion mixture was stirred for 0.5 h, poured in 100 ml of
water, the precipitate of manganese(IV) oxide was filtered
off, the filtrate was acidified with hydrochloric acid, the
separated precipitate was filtered off and dried.
2-Azido-1-phenyl-4-chloro-1Н-imidazole-5-
carboxylic acid (Ха). Yield 24%, mp 186–187°С. IR
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POLYFUNCTIONAL IMIDAZOLES: VI.
711
1
spectrum, cm–1: 2830–2550 (COOH), 2165 (N3), 1715
(С=О). 1Н NMR spectrum, δ, ppm: 7.33–7.49 m (5Нarom),
13.03 br.s (1Н, СООН). Found, %: C 45.33; H 2.11;
N 26.38. [M + 1]+ 264. С10H6СlN5O2. Calculated, %:
C 45.56; H 2.29; N 26.56. M 263.64.
cm–1: 3325 (NH2). Н NMR spectrum, δ, ppm: 5.56 s
(2Н, NH2), 6.84 s (Н5), 7.44 d (2Нarom, J 8.2 Hz), 7.60 d
(2Нarom, J 8.2 Hz). Found, %: C 47.72; H 3.21; N 18.65.
[M + 1]+ 228. С9H7Сl2N3. Calculated, %: C 47.40; H 3.09;
N 18.42. M 228.08.
2-Azido-4-chloro-1-(4-chlorophenyl)-1Н-imid-
azole-5-carboxylic acid (Хb). Yield 25%, mp 169–
170°С. IR spectrum, cm–1: 2850–2520 (COOH), 2160
1-(4-Methylphenyl)-4-chloro-1Н-imidazole-2-
amine (ХІc). Yield 63%, mp 138–139°С. IR spectrum,
1
cm–1: 3310 (NH2). Н NMR spectrum, δ, ppm: 5.63 s
1
(2Н, NH2), 6.87 s (Н5), 7.33 s (4Нarom). 13C NMR spec-
trum, δ, ppm: 20.51 (CH3), 110.18 (C5), 124.13, 130.00,
136.77, 147.39 (Carom), 124.79 (С2), 133.90 (С4). Found,
%: C 57.99; H 4.66; N 20.10. [M + 1]+ 208. С10H10СlN3.
Calculated, %: C 57.84; H 4.85; N 20.23. M 207.66.
(N3), 1710 (С=О). Н NMR spectrum, δ, ppm: 7.44 d
(2Нarom, J 7.8 Hz), 7.55 d (2Нarom, J 7.8 Hz), 13.10 br.s
(1Н, СООН). Found, %: C 40.06; H 1.77; N 23.62. [M +
1]+ 298. С10H5Сl2N5O2. Calculated, %: C 40.29; H 1.69;
N 23.79. M 298.09.
2-Azido-1-(4-methylphenyl)-4-chloro-1Н-
imidazole-5-carboxylic acid (Хc). Yield 24%, mp
173–175°С. IR spectrum, cm–1: 2870–2520 (COOH),
1-(4-Methoxyphenyl)-4-chloro-1Н-imidazole-2-
amine (ХІd). Yield 59%, mp 123–124°С. IR spectrum,
1
cm–1: 3320 (NH2). Н NMR spectrum, δ, ppm: 5.58 s
1
2165 (N3), 1715 (С=О). Н NMR spectrum, δ, ppm:
(2Н, NH2), 6.82 s (Н5), 7.04 d (2Нarom, J 8.8 Hz), 7.34 d
(2Нarom, J 8.8Hz). 13C NMR spectrum, δ, ppm: 55.42
(CH3О), 111.63 (C5), 115.84, 126.07, 130.95, 158.76
(Carom), 125.32 (С2), 134.58 (С4). Found, %: C 53.47;
H 4.72; N 18.59. [M + 1]+ 224. С10H10СlN3О. Calculated,
%: C 53.70; H 4.51; N 18.79. M 223.66.
2.37 s (3Н, СН3), 7.22–7.28 m (4Нarom), 12.99 br.s (1Н,
СООН). Found, %: C 47.76; H 2.73; N 25.34. [M + 1]+
278. С11H8СlN5O2. Calculated, %: C 47.58; H 2.90;
N 25.22. M 277.67.
2-Azido-1-(4-methoxyphenyl)-4-chloro-1Н-
imidazole-5-carboxylic acid (Хd). Yield 20%, mp
153–154°С. IR spectrum, cm–1: 2860–2520 (COOH),
2165 (N3), 1715 (С=О). 1Н NMR spectrum, δ, ppm: 3.82 s
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(3Н, СН3О), 6.99 d (2Нarom, J 8.4 Hz), 7.29 d (2Нarom
,
J 8.4 Hz), 13.00 br.s (1Н, СООН). Found, %: C 45.24;
H 2.70; N 23.68. [M + 1]+ 294. С11H8СlN5O3. Calculated,
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1-Aryl-4-chloro-1Н-imidazole-2-amines ХІа–XId.
To a solution of 1.7 g (7.5mmol) of tin(II) chloride dihy-
drate in 10 ml of 20% sodium hydroxide was added by
small portions at stirring while cooling to 0–5°С 5 mmol
of acid Ха–Xd, the reaction mixture was stirred at room
temperature for 0.5 h. The solution obtained was neutral-
ized with 10% solution of hydrochloric acid, the amine
was extracted into benzene (2 × 10 ml), the benzene
solution was dried with anhydrous sodium sulfate. The
solvent was evaporated, the residue was crystallized from
50% aqueous ethanol.
1-Phenyl-4-chloro-1Н-imidazole-2-amine (ХІа).
Yield 67%, mp 125–126°С. IR spectrum, cm–1: 3315
1
(NH2). Н NMR spectrum, δ, ppm: 5.62 s (2Н, NH2),
6.91 s (Н5), 7.39–7.51 m (5Нarom). Found, %: C 55.59;
H 4.08; N 21.57. [M + 1]+ 194. С9H8СlN3. Calculated,
%: C 55.83; H 4.16; N 21.70. M 193.64.
4-Chloro-1-(4-chlorophenyl)-1Н-imidazole-2-
amine (ХІb). Yield 69%, mp 106–107°С. IR spectrum,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012