Polyfunctional imidazoles: I. Synthesis of 1-substituted 4-chloro-1H-imidazole-5-carbaldehydes by Vilsmeier-haack reaction

Article abstract of DOI:10.1134/S1070428009080168

2-[Alkyl(aryl)amino]acetamides in reaction with Vilsmeier-Haack reagent afforded 1-alkyl(aryl)-4-chloro-1H-imidazole-5-carbaldehydes.

Full text of DOI:10.1134/S1070428009080168

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 8, pp. 1210−1213. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.A. Chornous, M.K. Bratenko, M.V. Vovk, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 8, pp. 1219−
1222.
Polyfunctional Imidazoles: I.
Synthesis of 1-Substituted 4-Chloro-1H-imidazole-5-carbaldehydes
by Vilsmeier-Haack Reaction
V. A. Chornousa, M. K. Bratenkoa, and M. V. Vovkb
aBukovina State Medical University, Chernovtsy, Ukraine
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094 Ukraine
e-mail: chornous@inbox.ru
Received July 1, 2008
Abstract—2-[Alkyl(aryl)amino]acetamides in reaction with Vilsmeier–Haack reagent afforded 1-alkyl(aryl)-4-
chloro-1H-imidazole-5-carbaldehydes.
DOI: 10.1134/S1070428009080168
chloro-3H-imidazole that in its turn was obtained by con-
densation of ethylpentane imidate hydrochloride with
dihydroxyacetone and ammonia at elevated temperature
and pressure followed by the chlorination into the position
4 of the imidazole ring with N-chlorosuccinimide [13].
The chloroformylation of 2-substituted imidazolin-5-ones
[6] with a Vilsmeier–Haack reagent although was
preparatively simple but required the application of
difficultly available alkyl imidates for the preparation of
the initial imidazolin-5-ones. One other procedure of the
synthesis of the 2-butyl-5-chloro-3H-imidazole-4-carb-
aldehyde [14] involved the use of 2-butylimidazole that
in five reaction stages was transformed into the target
product in 24% yield.
The methods of N1-alkylation were well developed
by the example of 2-substituted 5-chloro-3H-imidazole-
4-carbaldehydes [8–10]. At the same time the N1-aryl-
substituted 4-chloroimidazole-5-carbaldehydes with the
free position 2 of the heterocycle remain unknown. How-
ever they also due to the polyfunctional character are
important synthetic objects for a purposeful designing of
potentially bioactive substances. Therefore the present
report concerns the development of a synthetic procedure
for new 1-substituted 4-chloro-1H-imidazole-5-carb-
aldehydes.
Functional imidazole derivatives possess a consider-
able biological potential. They inhibit the HIV-1 reverse
transcriptase [1], cell fission [2], aldosterone biosynthesis
[3]. Especially important is their ability to act as non-
peptide antagonists of the angiotensin II receptors II [4]
that has been used in designing the drug losartan against
the arterial hypertension [5, 6]. The key synthon in
preparation of the latter was 2-butyl-4(5)-chloro-1H-
imidazole-5(4)carbaldehyde. In the synthesis of losartan
analogs [7–12] alongside this compounds also the other
2-alkyl(aryl)-4(5)-chloro-1H-imidazole-5(4)-carb-
aldehydes were employed.
Cl
N
OH
H
N
N N
N
N
To prepare 2-alkyl-4(5)-chloro-1H-imidazole-5(4)-
carbaldehydes unsubstituted at the position 1 (3) several
approaches were used, commonly multistage, requiring
special conditions and providing side products. In
particular, a synthesis was described of 2-butyl-5-chloro-
3H-imidazole-4-carbaldehyde by oxidation with manga-
nese(II) oxide of the corresponding 4-hydroxymethyl-5-
The Vilsmeier–Haack reaction was formerly succes-
sively applied to the synthesis of some α,β-chloroformyl-
functionalized nitrogen heterocycles. It was established
1210

POLYFUNCTIONAL IMIDAZOLES: I.
1211
O
N
Cl
NH2
N
DMF_POCl3
_
POCl3 H2O
RHN
CH
O
O
N
R
N
R
Me2N
Iа_Ij
IIа_IIj
IIIа_IIIj
R = Bu (a), PhCH2 (b), Ph (c), 2-MeC6H4 (d), 4-ClC6H4 (e), 4-BrC6H4 (f), 4-MeC6H4 (g), 4-MeOC6H4 (h), 2,5-Me2C6H3 (i),
1-naphthyl (j).
in particular that N-aryl-2-azidoacetamides in reaction
with a system DMF–POCl3 formed 1-aryl-2-(dimethyl-
amino)-5-chloro-1H-imidazole-4-carbaldehydes[15], and
N-acetylglycine gave 3,5-diformyl-2,4-dichloropyrrole
[16]. We investigated in this study the behavior in the
Vilsmeier–Haack reaction of available [17, 18] 2-amino-
substituted acetamides Ia–Ij that reacted with the mixture
of DMF and POCl3 in the molar ratio 1:2 at 90°C affording
1-substituted 4-chloro-1H-imidazole-5-carbaldehydes
IIa–IIj in 45–54% yields. Taking into consideration the
rules of the reaction of 1,4-bifunctional nitrogen nucleo-
philes with Vilsmeier–Haack reagent [19] it is presumable
that the interaction proceeds through a stage of inter-
mediate 1-substituted 5-dimethylaminomethyleneimid-
azolin-4-ones IIIa–IIIj that undergo further chlorination
and hydrolysis to yield the target compounds. This
assumption was confirmed by a special experiment that
provided a possibility to isolate from the reaction mixture
5-dimethylaminomethylene-1-(4-tolyl)imidazolin-4-one
(IIIg) at the ratio DMF–POCl3 1:1.
1-Aryl-4-chloro-1H-imidazole-5-carbaldehydes
IIa–IIj. To a suspension of 0.03 mol of acetamide Ia–Ih
in 6.75 g (0.09 mol) of DMF was added at stirring and
cooling to 0–5°C 26.7 g (0.18 mol) of phosphorus
oxychloride. The mixture obtained was heated for 4 h on
a water bath at 90°C. The excess phosphorus oxychloride
was removed in a vacuum, to the residue 50 ml of water
was added, and the solution was neutralized with
crystalline NaHCO3 till pH 8.0. The formed precipitate
was filtered off, the filtrate was extracted with ethyl
acetate (3×20 ml), the extract was evaporated, the
residue was combined with the precipitate, and the
mixture was dissolved in hexane–ethyl acetate, 3:1, the
solution was slowly filtered through a bed of alumina,
and then it was subjected to chromatography on alumina
(eluent hexane–ethyl acetate, 1:1) (in the case of com-
pound IIa) or crystallized from 60% aqueous ethanol (for
compounds IIb–IIj).
1-Butyl-4-chloro-1H-imidazole-5-carbaldehyde
(IIa). Yield 48%, viscous fluid. IR spectrum, cm–1: 1685
1
(C=O). H NMR spectrum, δ, ppm: 0.92 t (CH3), 1.24–
The composition and structure of all compounds
1
1.30 m (2H, CH2), 1.95–2.02 m (2H, CH2), 4.28 t (2H,
NCH2), 8.02 s (1H, H2), 9.74 s (1H, CH=O). 13C NMR
spectrum, δ, ppm: 13.43 (CH3), 19.50 (CH2), 32.75
(CH2), 47.80 (CH2), 124.46 (C5), 140.82 (C2), 142.93
(C4), 178.33 (CH=O). Found, %: C 51.16; H 12.03; N 14.82.
C8H11ClN2O. Calculated, %: C 51.48; H 11.88; N 15.01.
obtained were confirmed by elemental analyses , IR, H
1
and 13C NMR spectra. In particular, in the H NMR
spectra of compounds IIa–IIj singlet signals were observ-
ed from the protons H2 of the imidazole ring (7.62–
8.23 ppm) and from the formyl group (9.64–9.82 ppm).
The signals from the corresponding carbon atoms in the
13C NMR spectra appeared in the range 140–144 and
177 ppm, respectively.
1-Benzyl-4-chloro-1H-imidazole-5-carbaldehyde
(IIb). Yield 52%, mp 70–71°C. IR spectrum, cm–1: 1670
1
(C=O). H NMR spectrum, δ, ppm: 5.50 s (2H, CH2),
7.24–7.32 m (5Harom), 8.20 s (1H, H2), 9.71 s (1H, CH=O).
13C NMR spectrum, δ, ppm: 51.06 (CH2), 124.56 (C5),
127.89, 128.70, 129.10, 134.75 (CAr), 140.96 (C2), 143.14
(C4), 178.52 (CH=O). Found, %: C 60.11; H 4.27;
N 12.85. C11H9ClN2O. Calculated, %: C 59.88; H 4.11;
N 12.70.
EXPERIMENTAL
IR spectra of compound IIa in CH2Cl2 and of
compounds IIb–IIj in pellets with KBr were recorded
1
on a spectrophotometer UR-20. H NMR spectra in
DMSO-d6 were registered on a spectrometer Varian-
Gemini (299.94 MHz), internal reference TMS. 13C NMR
spectra in DMSO-d6 were registered on a spectrometer
BruketArano DRX-500 (125.75 MHz), internal reference
TMS.
1-Phenyl-4-chloro-1H-imidazole-5-carbaldehyde
(IIc). Yield 47%, mp 116–117°C. IR spectrum, cm–1: 1675
1
(C=O). H NMR spectrum, δ, ppm: 7.32 m (2Harom),
7.49 m (3Harom), 7.62 s (1H, H2), 9.82 s (1H, CH=O).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 8 2009

CHORNOUS et al.
1212
13C NMR spectrum, δ, ppm: 125.21 (C5), 125.72, 129.43,
129.69, 135.12 (CAr), 140.87 (C2), 142.80 (C4), 177.27
(CH=O). Found, %: C 58.39; H 3.47; N 13.75.
C10H7ClN2O. Calculated, %: C 58.13; H 3.41; N 13.56.
1-(2,5-Dimethylphenyl)-4-chloro-1H-imidazole-
5-carbaldehyde (IIi). Yield 51%, mp 110–111°C. IR
1
spectrum, cm–1: 1675. H NMR spectrum, δ, ppm: 1.98
s (3H, CH3), 2.34 s (3H, CH3), 7.12 s (1Harom), 7.26 s
(2Harom), 8.03 s (1H, H2), 9.64 s (1H, CH=O). 13C NMR
spectrum, δ, ppm: 16.78 (CH3), 20.75 (CH3), 125.87 (C5),
127.39, 130.86, 131.79, 134.38, 136.90 (CAr), 140.83 (C2),
141.78 (C4), 177.22 (CH=O). Found, %: C 61.19; H 4.85;
N 12.12. C12H11ClN2O. Calculated, %: C 61.41; H 4.72;
N 11.94.
1-(2-Methylphenyl)-4-chloro-1H-imidazole-5-
carbaldehyde (IId). Yield 45%, mp 105–106°C. IR
spectrum, cm–1: 1670 (C=O). 1H NMR spectrum, δ,
ppm: 2.05 s (3H, CH3), 7.16–7.42 m (4Harom), 7.51 s (1H,
H2), 9.76 s (1H, CH=O). 13C NMR spectrum, δ, ppm:
17.25 (CH3), 125.88 (C5), 126.92, 130.16, 131.11, 134.64,
135.09 (CAr), 140.87 (C2), 141.96 (C4), 177.22 (CH=O).
Found, %: C 60.07; H 4.29; N 12.61. C11H9ClN2O.
Calculated, %: C 59.88; H 4.11; N 12.70.
1-(1-Naphthyl)-4-chloro-1H-imidazole-5-
carbaldehyde (IIj). Yield 52%, mp 140–141°C. IR
spectrum, cm–1: 1680 (C=O). 1H NMR spectrum, δ,
ppm: 7.28 d (2Harom), 7.53–7.65 m (4Harom), 8.06–8.14
m (2Harom), 8.23 s (H2), 9.64 s (CH=O). Found, %: C
65.28; H 5.59; N 11.06. C14H9ClN2O. Calculated, %: C
65.51; H 3.53; N 10.91.
4-Chloro-1-(4-chlorophenyl)-1H-imidazole-5-
carbaldehyde (IIe). Yield 49%, mp 159–160°C. IR
spectrum, cm–1: 1675 (C=O). 1H NMR spectrum, δ, ppm:
7.27 d (2Harom), 7.45 d (2Harom), 7.61 s (1H, H2), 9.82 s
(1H, CH=O). 13C NMR spectrum, δ, ppm: 125.12 (C5),
127.03, 129.58, 133.63, 135.69 (CAr), 140.90 (C2), 142.25
(C4), 177.21 (CH=O). Found, %: C 50.04; H 2.37; N 11.70.
C10H6Cl2N2O. Calculated, %: C 49.82; H 2.51; N 11.62.
5-Dimethylaminomethylene-1-(4-tolyl)-1,5-di-
hydro-4H-imidazol-4-one (IIIg) was obtained in the
same way as compounds IIa–IIh, but at the use of equi-
molar mixture of DMF and POCl3. The reaction mixture
was heated on a water bath for 1 h instead of 4 h and at
60°C. Yield 57%, mp 156–157°C. IR spectrum, cm–1:
1-(4-Bromophenyl)-4-chloro-1H-imidazole-5-
carbaldehyde (IIf). Yield 54%, mp 176–177°C. IR
spectrum, cm–1: 1670 (C=O). 1H NMR spectrum, δ, ppm:
7.44 d (2Harom), 7.69 d (2Harom), 8.18 s (1H, H2), 9.71 s
(1H, CH=O). 13C NMR spectrum, δ, ppm: 125.11 (C5),
123.78, 127.28, 132.62, 134.15 (CAr), 143.38 (C2), 147.05
(C4), 177.26 (CH=O). Found, %: C 42.31; H 2.05; N
9.71. C10H6ΒrClN2O. Calculated, %: C 42.07; H 2.12;
N 9.81.
1
1650 (C=C), 1695 (C=O). H NMR spectrum, δ, ppm:
2.34 s (3H, CH3), 3.25 s (3H, CH3), 3.51 s (3H, CH3),
7.19 s (1H, CH=), 7.22 d (2Harom), 7.46 d (2Harom),
7.73 s (1H, H2). Found, %: C 67.86; H 6.42; N 18.57
C13H15N3O. Calculated, %: C 68.10; H 6.59; N 18.32.
REFERENCES
1-(4-Methylphenyl)-4-chloro-1H-imidazole-5-
carbaldehyde (IIg). Yield 49%, mp 117–118°C. IR
spectrum, cm–1: 1665 (C=O). 1H NMR spectrum, δ, ppm:
2.36 s (3H, CH3), 7.33 m (4Harom), 8.11 s (1H, H2), 9.67
s (1H, CH=O). 13C NMR spectrum, δ, ppm: 21.25 (CH3),
121.39 (C5), 125.30, 130.01, 132.60, 139.96 (CAr), 140.85
(C2), 142.69 (C4), 177.35 (CH=O). Found, %: C 59.59;
H 4.33; N 12.53. C11H9ClN2O. Calculated, %: C 59.88;
H 4.11; N 12.70.
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