Polyfunctional Imidazoles: II.* synthesis and reactions with nucleophilic reagents of 1-substituted 2,4-Dichloro-1H-imidazole-5-carbaldehydes

Article abstract of DOI:10.1134/S1070428011050083

1-Alkyl(aryl)imidazolidine-2,4-diones reacted with Vilsmeier-Haack reagent affording 1-alkyl(aryl)-2,4-dichloro-1H-imidazole-5-carbaldehydes whose reactions with sodium azide, sodium alkoholates, with phenols, thiols, and secondary cycloalkylamines led to the substitution of chlorine in the position 2 of the imidazole ring. The reaction with primary amines resulted in the condensation products at the aldehyde group. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011050083

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 5, pp. 702−709. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.A. Chornous, A.M. Grozav, E.B. Rusanov, A.M. Nesterenko, M.V. Vovk, 2011, published in Zhurnal Organicheskoi Khimii, 2011,
Vol. 47, No. 5, pp. 699−706.
Polyfunctional Imidazoles: ІІ.* Synthesis and Reactions
with Nucleophilic Reagents of 1-Substituted
2,4-Dichloro-1Н-imidazole-5-carbaldehydes
V. A. Chornousa, A. M. Grozava, E. B. Rusanovb, A. M. Nesterenkob, and M. V. Vovkb
a Bukovinskii State Medical University, Chernovtsy, Chernovtsy, 58000 Ukraine
e-mail: chornous@inbox.ru
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine
Received March 4, 2010
Abstract—1-Alkyl(aryl)imidazolidine-2,4-diones reacted with Vilsmeier–Haack reagent affording 1-alkyl(aryl)-
2,4-dichloro-1Н-imidazole-5-carbaldehydes whose reactions with sodium azide, sodium alkoholates, with phenols,
thiols, and secondary cycloalkylamines led to the substitution of chlorine in the position 2 of the imidazole ring.
The reaction with primary amines resulted in the condensation products at the aldehyde group.
DOI: 10.1134/S1070428011050083
Polyhalogenated derivatives of imidazoles exhibit
a number of valuable biological actions. Among them
compounds were detected with antiviral [2] and insecti-
cidal activity [3], and also selective inhibitors of cyclo-
oxygenase [4]. In a series of recent patents their efficiency
was stated as glutamate receptor antagonists in the treat-
ment of neurological disorders [5], as chemotherapeutic
agents [6], specific inhibitors of HIV proliferation [7],
and selective fungicides [8, 9].
2,4-diones (hydantoins) [10–12] with Vilsmeier-Haack
reagent. It was established that at heating at 90°С for 6 h
of imidazolidine-2,4-diones Iа–Ig with DMF and РОСl3
in the ratio 1:2:5 followed by hydrolysis 2,4-dichloro-
1-aryl(alkyl)-1Н-imidazole-5-carbaldehydes IIа–IIg
formed in 47–52% yield. The reaction most probably pro-
ceeded through the formation of intermediates of А type
which under the action of excess phosphorus oxychloride
were converted into target compounds II (Scheme 1). This
result is distinguished from the Vilsmeier-Haack reaction
with 3-arylimidazolidine-2,4-diones that stopped at the
formation of 5-chloro-2-oxo-2,3-dihydro-1Н-imidazole-
4-carbaldehydes [13].
The preparation of imidazole 2,4-dihalogen deriva-
tives with aromatic (heteroaromatic) substituents in the
positions 1 and 5 of the ring was suggested to proceed
out by the radical chlorination or bromination with
N-halosuccinimides [8, 9]. Yet this procedure cannot be
applied in the presence of some labile functional sub-
stituents whose presence in the imidazole ring alongside
the halogen atoms can significantly extend the synthetic
potential of the heterocycle. Formyl moieties belong
first of all to these groups for they are prone to versatile
chemical modifications.
The presence of an aldehyde group in the chlorinated
imidazoles IIа–IIg was confirmed by IR spectra con-
taining the absorption bands at 1680–1685 cm–1, and by
1Н NMR spectra with characteristic singlets in the region
9.52–9.69 ppm. In the 13С NMR spectra the aldehyde
group gave rise to the signal at 175–177 ppm.
Compounds II are imidazole derivatives with three
reaction sites, and it should be expected that the reactions
with nucleophilic reagents would be most typical for
them. Therewith the published data on the transforma-
tions of 2,4,5-trihalo-substituted imidazoles were limited
to reactions with butyllithium and electrophilic reagents
We developed a simple version of preparation of im-
idazole 5-formyl-2,4-dichloro derivatives consisting in
the formylation of available 1-alkyl-(aryl)imidazolidine-
____________________
* For Communication I, see [1].
702

POLYFUNCTIONAL IMIDAZOLES: ІІ.
703
Table 1. Charges on atoms С2 and С4 of compound IIa and
contributions of atomic orbitals 2pz into LUMO
Scheme 1.
O
Cl
Characteristics
С2
С4
POCl3_DMF
HN
HN
Contributions of atomic orbitals 2pz into
LUMO (of π-type)
–0.243 0.297
O
O
CH O
N
R
Iа_Ig
N
R
A
Charge on carbon atom according to Mul- –0.048 –0.215
liken
Charge on carbon atom according to NBO
0.352 0.319
Cl
N
Charge on carbon atom according to
0.336 0.311
POCl3
Merz−Kollman
Cl
CH O
N
R
IIа_IIg
adjusted with the aim to describe the most precise the dis-
tribution of the electrostatic potential near the molecule.
It is known that at the orbital control of a reaction
the contribution of the interacting atomic orbitals of the
reagents into the energy of stabilization of the transition
state is proportional to the squares of the corresponding
coefficients of the atomic orbitals in the frontier molecular
orbitals. The results we obtained show that due to rela-
tively small difference in the coefficients of the atomic
orbitals of atoms С2 and С4 in LUMO it is expectable that
even with the “soft” nucleophiles this stabilization would
not be decisive for the reaction direction, i.e., the process
would be controlled by the charge distribution.Although
the charge values calculated by Mulliken method are
not sufficiently reliable (the carbon atoms have negative
charge), the comparison of the charge distribution shows
that notwithstanding of the calculation method the elec-
tron density on the atom С2 is significantly lower than
on the atom С4. This should result in the predominant
attack of the nucleophilic reagents on the position 2 of
compounds II. This assumption was corroborated by
the study of the reactions of these compounds with the
following highly nucleophilic reagents: sodium azide,
sodium alkoholates ІІІа–IIIe, phenols IIIf, IIIg, thiols
IVа–IVc, and also secondary aliphatic amines Vа–Vc.
R = Mе (а), Рh (b), 4-FС6Н4 (c), 4-СlС6Н4 (d), 2-MеС6Н4 (e),
4-MеС6Н4 (f), 4-MеОС6Н4 (g).
which led to the substitution of the halogen either in the
position 2 [14] or the position 4 [15] of the ring.
We estimated the reactivity and selectivity of reactions
of imidazoles II with versatile nucleophiles by a quantum-
chemical investigation of the molecule of 1-methyl-2,4-
dichloro-5-formylimidazole (ІІа) in the processes of the
chlorine substitution at the prevalence of orbital or charge
control of the reaction [16]. In the event of the dominant
role of the orbital control the relative reactivity of the
chlorine atoms in the positions 2 and 4 of the molecule
with respect to the nucleophilic reagents would first of
all depend on the size of the contribution of the atomic
orbitals of the attacked sites (atoms С2 and С4) into the
lowest unoccupied molecular orbital where the electron
density from the molecular orbital of the nucleophile
would be transferred. In the case of the charge control the
nucleophilic substitution is expected at the carbon atom
possessing the highest positive charge.
Aiming at revealing which factor would govern the
direction of chlorine substitution we calculated the elec-
tron distribution in compound IIa in the approximation
of the density matrix by B3LYP method in the basis
6-31++G(d,p) using GAUSSIAN-3W software [17].
We demonstrated that 2,4-dichloroimidazole-
carbaldehydes IIа–IIg in the reaction with 2.5-
fold excess of sodium azide in DMF at room tem-
perature formed 2-azido-4-chloro-1Н-imidazole-
4-carbaldehydes VIа–VIg in 80–95% yields. The
replacement of the chlorine atom in the position 2 of
aldehydes IIa, IIb, IId, and IIg by alkoxy groups that
should proceed at heating these compouns with sodium
alcoholated ІІІа–IIIe in the solution of the corresponding
alcohol les to the formation of the respective 2-alkoxy-
substituted derivatives VIIа–VIIe. The attempt to obtain
The data suggesting the prevailing direction of the
reaction are presented in Table 1. LUMO corresponds to
the π-type that has simplified the analysis of the respec-
tive contributions into the energy of the transition state
[16]. The charges on atoms С2 and С4 were calculated by
different procedures: by the traditional Mulliken method,
by NBO method [18], and by Merz−Kollman method
[19, 20] where the magnitude of charges on the sites was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

CHORNOUS et al.
704
group was involved into the reaction furnishing 5-imino
derivatives of imidazole ХІа–XId (Scheme 2).
2-aryloxyimidazoles VIIf–VIIg by the reaction with
sodium phenolates in boiling ethanol failed. In all cases
2-ethoxyimidazole VIIc was obtained. We believe that
this direction of the reaction is due to the proceeding of
the process by the mechanism SN1arom of nucleophilic
substitution of the chlorine atom in the position 2 of the
imidazole ring [21]. Yet compounds VIIf–VIIg were syn-
thesized by heating dichloroimidazoles IIb and IIg with
the corresponding phenols in boiling DMF in the presence
of equimolar quantity of potassium carbonate.At the same
time softer thiols IVа–IVc at boiling for 1 h in ethanol
in the presence of sodium hydroxide by selectively sub-
stituted the chlorine in the position 2 of the imidazole
ring forming 2-alkyl-(aryl)sulfanyl-4-chloroimidazole-
5-carbaldehydes VIIIа–VIIId in 61–74% yields.
The substitution of the chlorine atoms in the position
2 of the imidazole ring by donor moieties affected the
chemical shifts of atoms С2 in the 13С NMR spectra. In
particular, in the spectra of 2-ethoxy- (VIIc), 2-phenoxy-
(VIIf), 2-morpholino-(IXa), and 2-piperidino-substituted
derivatives (IXb) these signals are shifted downfield to
δ 152–153 ppm. In the spectra of 2-sulfanyl derivatives
VIIIc and VIIId the corresponding signals of atoms С2
are at δ 147–150 ppm. The azido group of compounds
III virtually does not affect the magnetic behavior of
atoms С2, and they appear in the same position as in
the initial 2,4-dichloroimidazolecarbaldehydes II, at
δ 138 ppm. However we proved the actual formation
of 2-azidoaldehydes by XRD analysis by an example
of compound VIb. Its crystals are monoclinic, space
group Р21/с, а 19.240(4), b 6.6641(13), c 18.381(3) Ǻ,
β 110.483(10)°, V 2207.8(7) Ǻ3, Z 8 (two independent
molecules), dc 1.49 g/cm3, μ 0.336 mm–1, F(000) 1008.
The most interesting are the results obtained in the
reactions with amines where both chlorine atoms in the
position 2 and aldehyde group are reactive. In particular,
highly basic secondary cyclic amines Vа–Vc in boiling
ethanol reacted with the replacement of chlorine atom
giving 2-amino derivatives IXа–IXc. With less basic
primary alkyl- and arylamines Ха–Xd disregarding the
reaction conditions and the reagents ratio oly the aldehyde
The distribution of bond lengths and bond angles in the
central imidazole ring (see the figure) has no special fea-
tures and is usual for such systems. The main geometric
Scheme 2.
Cl
Cl
Cl
N
N
N
R2
O
N3
R2
S
N
N
R1
N
R1
O
O
O
R1
VIIа_VIIg
VIIIа_VIIIg
VIа_VIg
IIа_IIg
R2SH
IVа_IVc
R2ONa or R2OH
IIIа_IIIe IIIf, IIIg
Cl
N
Cl
N
R2R3NH
Vа_Vc
R2NH2
R2R3N
Xа_Xd
Cl
N
O
N
R1
N R2
R1
IXа_IXc
XIа_XId
ІІІ, R2 = Me (a), Et (b), Bu (c), iso-С5Н11 (d), СН2Рh (e), Ph (f), 4-MeC6H4 (g); IV, R2 = cyclo-С6Н11 (а), СН2СООН (b), 4-ClC6H4 (c);
V, R2,R3 = (CH2)5 (a), (CH2)2O(CH2)2 (b), 1-СН2-2-(СН2)2С6Н4 (c); VI, R1 = Me (a), Ph (b), 4-FC6H4 (c), 4-ClC6H4 (d), 2-MеС6Н4 (e),
4-MеС6Н4 (f), 4-MеОС6Н4 (g); VII, R1 = Me, R2 = CH2Ph (a); R1 = Ph, R2 = Me (b), Et (c), Bu (d); R1 = 4-ClC6H4, R2 = iso-С5Н11 (e);
R1 = R2 = Ph (f); R1 = 4-MeOC6H4, R2 = 4-MeC6H4 (g); VIII, R1 = Me, R2 = 4-ClC6H4 (a); R1 = Ph, R2 = cyclo-С6Н11 (b), СН2СООН
(c), 4-СlC6H4 (d); IX, R1 = Ph, R2,R3 = (CH2)2O(CH2)2 (а); R1 = 4-ClC6H4, R2,R3 = (CH2)5 (b); R1 = 4-MeC6H4, R3,R3 = 1-CH2-2-
(CH2)2C6H4 (c); X, R2 = Me (a), СН2СН2ОН (b), Ph (c), 4-MеС6Н4 (d); XI, R1 = Ph, R2 = Me (a); R1 = 4-СlС6Н4, R2 = СН2СН2ОН
(b); R1,R2 = Рh (c); R1 = 4-MеОС6Н4, R2 = 4-MеС6Н4 (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

POLYFUNCTIONAL IMIDAZOLES: ІІ.
705
Table 2. Bond distances (Å) in two independent molecules А
and В of compound VIb
Bond
Molecule А
Molecule В
C1–N2/C11–N6
C1–N1/C11–N7
C1–N3/C11–N8
C2–N2/C12–N7
C2–C3/C12–C13
C2–Cl1/C12–Cl2
C3–N1/C13–N6
C3–C4/C13–C14
C4–O1/C14–O2
N3–N4/N8–N9
N4–N5/N9–N10
1.298(7)
1.352(8)
1.407(9)
1.347(8)
1.374(8)
1.719(6)
1.386(8)
1.449(9)
1.218(7)
1.237(8)
1.136(8)
1.335(7)
1.342(8)
1.371(8)
1.346(8)
1.377(8)
1.704(6)
1.397(8)
1.416(8)
1.231(7)
1.230(8)
1.130(8)
Table 3. Bond angles (deg) in two independent molecules А
and В of compound VIb
Angle
Molecule А
Molecule В
N2C1N1/N6C11N7
N2C2C3/N7C12C13
C2C3N1/Cl2Cl3N6
C1N1C3/C11N6C13
C1N2C2/C11N7C12
N4N3C1/N9N8C11
N5N4N3/N10N9N8
115.3(6)
113.2(5)
103.8(6)
105.0(5)
102.6(5)
111.5(6)
174.5(8)
113.3(6)
113.4(6)
103.2(5)
107.1(5)
103.0(5)
113.6(6)
171.2(8)
General view of the molecule of 2-azido-1-phenyl-4-chloro-
1Н-imidazole-5-carbaldehyde (VIb). For the sake of simplic-
ity only one independent molecule is shown, the second one
is similar.
parameters are compiled in Tables 2, 3. The heterocycle
proper is planar, the average deviation of atoms from the
mean-square plane amounts to 0.004 and 0.003 Å for
independent molecules А and В.
the direct method and refined with the use of programs
SHELXS97 and SHELXL97 [22, 23] by the least-squares
method in the full-matrix isotropic approximation for
disordered carbon atoms of the phenyl substituents, the
other nonhydrogen atoms were refined anisotropically.
Phenyl substituents of both independent molecules are
disordered by two positions with populations 57 and
43 for molecule А and 60 and 40% for molecule В. All
hydrogen atoms were placed geometrically and their
positions and thermal parameters were refined together
with the positions and parameters of the corresponding
carbon atoms. In the refining 1663 reflections was used
with I > 2σ(I), 248 refined parameters, 6.7 reflections
per a parameter, weighing scheme used ω = 1/[σ2(Fo2) +
EXPERIMENTAL
IR spectra of compounds were recorded on a spectro-
photometer UR-20 from pellets with KBr or solutions in
СН2Сl2. 1Н and 13С NMR spectra were recorded on spec-
trometer BrukerAdvance DRX-500 (500.13, 125.75 MHz
respectively), internal reference TMS. GC-MS measure-
ments were carried out on an instrument Agilent 1100/
DAD/HSD/VLG 119562.
The XRD analysis of a single crystal of compound
VIb of linear dimensions 0.03 × 0.23 × 0.27 mm was per-
formed at room temperature on a diffractometer Bruker
Smart Apex II (λMoKα-radiation,graphite monochroma-
tor, θmax 26.0°, spherical segment ≤ h ≤ 23, –7 ≤ k ≤ 8,
–18 ≤ l ≤ 22). Overall 12781 reflections was collected,
among them 4324 independent (R-factor of averaging
0.0794). The correction for extinction was done by the
program SADABS (ratio of minimal to maximal correc-
tion Tmin/Tmax 0.226520). The structure was solved by
(0.1014Р)2] where Р = (Fo2 + 2Fc )/3 is the ratio of the
2
maximum (average) shift to the error in the last cycle
0.080 (0.004). The final values of the divergence factors
are R1(F) 0.0917, wR2(F2) 0.2086, for I > 2σ(I) and R1(F)
0.1153, wR2(F2) 0.2250, GOF 0.997 for all reflections.
The residual electron density from the Fourier series
difference after the last cycle of refinement is 0.51 and
–0.55 е/Å3.
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CHORNOUS et al.
706
1-Alkyl(aryl)-2,4-dichloro-1Н-imidazole-5-
N 10.14. M 275.5.
carbaldehydes IIа–IIg. To a dispersion of 0.03 mol
of hydantoin Iа–Ig in 4.38 g (0.06 mol) of DMF while
stirring and cooling to 0–5°С was added 23 g (0.15 mol)
of phosphorus oxychloride. The mixture obtained was
heated on a water bath at 90°С for 8 h. Excess phosphorus
oxychloride was removed in a vacuum, the residue was
diluted with 50 ml of water and was neutralized with
crystalline NaHCO3 till рН 8.0. The formed precipitate
was filtered off, the filtrate was extracted with ethyl ac-
etate (3 × 20 ml), the extract was evaporated, the residue
was combined with the precipitate. The obtained reaction
product was chromatographed on aluminum oxide (eluent
hexane–ethyl acetate, 1:1) and afterwards crystallized
from 60% aqueous ethanol.
1-(2-Methylphenyl)-2,4-dichloro-1Н-imidazole-
5-carbaldehyde (IIe). Yield 50%, mp 85–88°С. IR
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum, δ,
ppm: 2.03 s (3Н, СН3), 7.36–7.52 m (4Нarom), 9.56 s
(1Н, СН=О). 13C NMR spectrum, δ, ppm: 17.24 (CH3),
127.25, 127.39, 130.67, 131.31, 133.41, 135.47 (СAr),
127.45 (C5), 138.61 (C2), 140.59 (C4), 176.07 (CH=O).
Found, %: C 51.70; H 3.24; N 10.81. [M + 1]+ 256.
С11H8Cl2N2O. Calculated, %: C 51.79; H 3.16; N 10.98.
M 255.1.
1-(4-Methylphenyl)-2,4-dichloro-1Н-imidazole-
5-carbaldehyde (IIе). Yield 48%, mp 99–100°С. IR
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum, δ,
ppm: 2.45 s (3Н, СН3), 7.34–7.39 m (4Нarom), 9.52 s
(1Н, СН=О). 13C NMR spectrum, δ, ppm: 21.37 (CH3),
126.87, 130.22, 131.31, 140.68 (СAr), 127.57 (C5), 138.67
(C2), 140.55 (C4), 176.16 (CH=O). Found, %: C 51.72;
H 3.10; N 10.89. [M + 1]+ 256. С11H8Cl2N2O. Calculated,
%: C 51.79; H 3.16; N 10.98. M 255.1.
1-Methyl-2,4-dichloro-1Н-imidazole-5-
carbaldehyde (IIа). Yield 49%, mp 52–54°С. IR
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum, δ,
ppm: 3.86 s (3Н, СН3), 9.69 s (1Н, СН=О). 13C NMR
spectrum, δ, ppm: 33.49 (CH3), 126.41 (C5), 134.61
(C2), 141.11 (C4), 177.39 (CH=O). Found, %: С 33.31;
H 2.30; N 15.51. [M + 1]+ 180. С5H4Cl2N2O. Calculated,
%: C 33.55; H 2.25; N 15.65. M 179.0.
1-(4-Methoxyphenyl)-2,4-dichloro-1Н-imidazole-
5-carbaldehyde (IIg). Yield 51%, mp 64–66°С. IR
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum, δ,
1-Phenyl-2,4-dichloro-1Н-imidazole-5-carb-
aldehyde (IIb). Yield 52%, mp 110–112°С. IR spectrum,
ν, cm–1: 1680 (С=О). 1Н NMR spectrum, δ, ppm: 7.48–
7.67 m (5Нarom), 9.54 s (1Н, СН=О). 13C NMR spectrum,
δ, ppm: 127.19, 129.59, 130.36, 133.93 (CAr), 127.56
(C5), 138.58 (C2), 140.65 (C4), 176.07 (CH=O). Found,
%: C 49.60; H 2.55; N 11.78. [M + 1]+ 242. С10H6Cl2N2O.
Calculated, %: C 49.82; H 2.51; N 11.62. M 241.0.
ppm: 3.87 s (3Н, СН3О), 7.08–7.41 m (4Нarom), 9.52 s
(1Н, СН=О). 13C NMR spectrum, δ, ppm: 55.61 (CH3O),
114.74, 126.39, 128.32, 160.79 (СAr), 127.66 (C5), 138.94
(C2), 140.53 (C4), 176.23 (CH=O). Found, %: C 48.96;
H 2.91; N 10.19. [M + 1]+ 272. С11H8Cl2N2O2. Calcu-
lated, %: C 48.73; H 2.97; N 10.33. M 271.1.
2-Azido-1-alkyl(aryl)-4-chloro-1Н-imidazole-5-
carbaldehydes VIа–VIg. To a solution of 5 mmol of
aldehyde IIа–IIg in 10 ml of DMF was added 0.8 g
(12.5 mmol) of sodium azide, and the mixture was stirred
at room temperature for 12 h. The reaction mixture was
poured into 100 ml of water, the formed precipitate was
filtered off, dried, and crystallized from 60% aqueous
ethanol.
1-(4-Fluorophenyl)-2,4-dichloro-1Н-imidazole-5-
carbaldehyde (IIc). Yield 49%, mp 123–125°С. IR spec-
trum, ν, cm–1: 1680 (С=О). 1Н NMR spectrum, δ, ppm:
7.38–7.58 m (4Нarom), 9.57 s (1Н, СН=О). 13C NMR
spectrum, δ, ppm: 116.73 d (2JС-F 22.6 Hz), 127.54,
1
129.12, 163.31 d (CAr, JС-F 251.5 Hz), 129.92 (C5),
138.93 (C2), 141.12 (C4), 176.03 (CH=O). Found, %:
C 46.50; H 1.87; N 10.64. [M + 1]+ 260. С10H5Cl2FN2O.
Calculated, %: C 46.36; H 1.95; N 10.81. M 259.0.
2-Azido-1-methyl-4-chloro-1Н-imidazole-5-
carbaldehyde (VIа). Yield 80%, mp 70–72°С. IR spec-
trum, ν, cm–1: 2150 (N3), 1680 (С=О). 1Н NMR spectrum,
δ, ppm: 3.61 s (3Н, СН3), 9.61 s (1Н, СН=О). Found, %:
С 32.30; H 2.27; N 37.62. С5H4ClN5O. Calculated, %:
С 32.36; H 2.17; N 37.74.
1-(4-Chlorophenyl)-2,4-dichloro-1Н-imidazole-
5-carbaldehyde (IId). Yield 51%, mp 135–137°С. IR
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum,
δ, ppm: 7.53–7.63 m (4Нarom), 9.58 s (1Н, СН=О).
13C NMR spectrum, δ, ppm: 127.45 (C5), 128.49, 129.87,
132.41, 136.58 (CAr), 138.79 (C2), 141.28 (C4), 175.99
(CH=O). Found, %: C 43.27; H 1.72; N 10.25. [M + 1]+
276. С10H5Cl3N2O. Calculated, %: C 43.59; H 1.83;
2-Azido-1-phenyl-4-chloro-1Н-imidazole-5-
carbaldehyde (VIb). Yield 89%, mp 138–140°С. IR
1
spectrum, ν, cm–1: 2155 (N3), 1685 (С=О). Н NMR
spectrum, δ, ppm: 7.47–7.53 m (5Нarom), 9.54 s (1Н,
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POLYFUNCTIONAL IMIDAZOLES: ІІ.
707
СН=О). 13C NMR spectrum, δ, ppm: 124.68 (C5), 127.07,
128.92, 129.45, 132.95 (CAr), 138.84 (C2), 144.90 (C4),
175.94 (CH=O). Found, %: С 48.31; H 2.49; N 28.36.
С10H6ClN5O. Calculated, %: С 48.50; H 2.44; N 28.48.
mixture was heated on a boiling water bath for 3 h. The
solvent was evaporated at a reduced pressure, the residue
was diluted with 50 ml of water, formed recipitate (com-
pounds VІIа–VIIc) was filtered off, dried, and crystal-
lized from aqueous ethanol. Oily products VIId and VIIe
were extracted into dichloromethane, dried with Nа2SО4,
the solvent was evaporated, the residue was subjected to
chromatography on neutral alumina, eluent hexane.
2-Azido-1-(4-fluorophenyl)-4-chloro-1Н-
imidazole-5-carbaldehyde (VIc). Yield 95%, mp 135–
137°С. IR spectrum, ν, cm–1: 1680 (С=О), 2155 (N3).
1Н NMR spectrum, δ, ppm: 7.28 d (1Нarom, J 8.7 Hz),
7.31 d (1Нarom, J 8.7 Hz), 7.43–7.48 m (2Нarom), 9.53 s
(1Н, СН=О). 13C NMR spectrum, δ, ppm: 115.88 d
(2JС-F 24.4 Hz), 124.80 (C5), 129.51, 129.58, 163.20 d
2-Benzyloxy-1-methyl-4-chloro-1H-imidazole-5-
carbaldehyde (VІIа). Yield 53%, mp 67–70°С. IR spec-
trum, ν, cm–1: 1685 (С=О). 1Н NMR spectrum, δ, ppm:
3.60 s (3Н, СН3), 5.44 s (2Н, СН2), 7.32–7.47 m (5Нarom),
9.55 s (1Н, СН=О). Found, %: C 57.41; H 4.48; N 10.99.
С12H11ClN2O2. Calculated, %: C 57.50; H 4.42; N 11.17.
1
(CAr, JС-F 252.0 Hz), 138.99 (C2), 145.12 (C4),
176.14 (CH=O). Found, %: С 45.01; H 1.98; N 26.17.
С10H5ClFN5O. Calculated, %: С 45.22; H 1.90; N 26.36.
2-Methoxy-1-phenyl-4-chloro-1H-imidazole-5-
carbaldehyde (VІIb). Yield 57%, mp 107–109°С. IR
2-Azido-1-(4-chlorophenyl)-4-chloro-1Н-
imidazole-5-carbaldehyde (VId). Yield 93%, mp 100–
102°С. IR spectrum, ν, cm–1: 2150 (N3), 1680 (С=О).
1Н NMR spectrum, δ, ppm: 7.47–7.54 m (4Нarom), 9.54 s
(1Н, СН=О). Found, %: С 42.50; H 1.68; N 24.88.
С10H5Cl2N5O. Calculated, %: С 42.58; H 1.79; N 24.83.
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum, δ,
ppm: 4.01 s (3Н, СН3), 7.36–7.46 m (5Нarom), 9.50 s
(1Н, СН=О). Found, %: C 55.65; H 3.69; N 11.75.
С11H9ClN2O2. Calculated, %: C 55.83; H 3.83; N 11.84.
2-Ethoxy-1-phenyl-4-chloro-1H-imidazole-5-
carbaldehyde (VІIc). Yield 59%, mp 82–84°С. IR
2-Azido-1-(2-methylphenyl)-4-chloro-1Н-
imidazole-5-carbaldehyde (VIe). Yield 84%, mp
68–70°С. IR spectrum, ν, cm–1: 2150 (N3), 1685 (С=О).
1Н NMR spectrum, δ, ppm: 2.02 s (3Н, СН3), 7.24–
7.44 m (4Нarom), 9.52 s (1Н, СН=О). Found, %: С 50.40;
H 3.17; N 26.71. С11H8ClN5O. Calculated, %: С 50.49;
H 3.08; N 26.76.
1
spectrum, ν, cm–1: 1680 (С=О). Н NMR spectrum,
δ, ppm: 1.30 t (3Н, СН3, J 6.6 Hz), 4.44 q (2Н, СН2,
J 6.6 Hz), 7.34–7.48 m (5Нarom), 9.50 s (1Н, СН=О).
13C NMR spectrum, δ, ppm: 14.11 (CH3), 67.46 (CH2),
122.18 (C5), 127.07, 128.79, 128.83, 133.10 (CAr),
138.73 (C4), 153.48 (C2), 175.34 (CH=O). Found, %:
C 57.27; H 4.38; N 11.34. С12H11ClN2O2. Calculated, %:
C 57.50; H 4.42; N 11.17.
2-Azido-1-(4-methylphenyl)-4-chloro-1Н-
imidazole-5-carbaldehyde (VIf). Yield 87%, mp 95–
100°С. IR spectrum, ν, cm–1: 2150 (N3), 1680 (С=О).
1Н NMR spectrum, δ, ppm: 2.39 s (3Н, СН3), 7.23–
7.30 m (4Н, Нarom), 9.50 s (1Н, СН=О). Found, %:
С 50.42; H 3.09; N 26.68. С11H8ClN5O. Calculated, %:
С 50.49; H 3.08; N 26.76.
2-Butoxy-1-phenyl-4-chloro-1H-imidazole-5-carb-
aldehyde (VІIId). Yield 54%, oily substance. IR spec-
trum, ν, cm–1: 1685 (С=О). 1Н NMR spectrum, δ, ppm:
0.88 t (3Н, СН3, J 6.0 Hz), 1.35 q (2Н, СН2, J 6.0 Hz),
1.65 t (2Н, СН2, J 6.0 Hz), 4.37 t (2Н, СН2, J 6.0 Hz),
7.25–7.46 m (5Нarom), 9.51 s (1Н, СН=О). Found, %:
C 60.53; H 5.49; N 10.15. С14H15ClN2O2. Calculated,
%: C 60.33; H 5.42; N 10.05.
2-Azido-1-(4-methoxyphenyl)-4-chloro-1Н-
imidazole-5-carbaldehyde (VIg). Yield 86%, mp 68–
70°С. IR spectrum, ν, cm–1: 2155 (N3), 1685 (С=О).
1Н NMR spectrum, δ, ppm: 3.83 s (3Н, СН3О),
6.99–7.31 m (4Нarom), 9.50 s (1Н, СН=О). 13C NMR
spectrum, δ, ppm: 55.44 (CH3O), 124.89 (C5), 114.13,
125.50, 128.42, 159.79 (СAr), 138.45 (C2), 145.01 (C4),
176.15 (CH=O). Found, %: С 47.40; H 2.74; N 25.03.
С11H8ClN5O2. Calculated, %: С 47.58; H 2.90; N 25.22.
2-Isopentoxy-1-(4-chlorophenyl)-4-chloro-1H-
imidazole-5-carbaldehyde (VІIIe). Yield 58%, oily
substance. IR spectrum, ν, cm–1: 1685 (С=О). 1Н NMR
spectrum, δ, ppm: 0.88 d (6Н, СН3, J 6.3 Hz), 1.54–
1.59 m (2Н, СН2), 1.63–1.71 m (1Н, СН), 4.36 t (2Н,
СН2, J 6.3 Hz), 7.26 d (2Нarom, J 7.8 Hz), 7.49 d (2Нarom
,
1-Alkyl(aryl)-2-alkoxy-4-chloro-1H-imidazole-
5-carbaldehydes VІIа–VIIe. To a solution of sodium
alcoholate obtained by dissolving 0.12 g (5.1mmol) of
metallic sodium in 10 ml of an appropriate alcohol was
added 5 mmol of aldehyde IIa, IIb, IId, IIg, and the
J 7.8 Hz), 9.50 s (1Н, СН=О). Found, %: C 55.31; H 4.80;
N 8.41. С15H16Cl2N2O2. Calculated, %: C 55.06; H 4.93;
N 8.56.
1-Aryl-2-aryloxy-4-chloro-1H-imidazole-5-carb-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

CHORNOUS et al.
708
[(4-Chloro-5-formyl-1-phenyl-1H-imidazol-2-yl
)
aldehydes VIIе and VIIg. To a solution of 0.48 g
(5.1 mmol) of phenol in 10 ml of DMF was added 0.7 g
(5.1 mmol) of potassium carbonate, 1.2 g (5 mmol) of al-
dehyde IIb or IIg, the mixture was boiled for 2 h, cooled,
and poured in water. The obtained precipitate was filtered
off, dried, and crystallized from aqueous ethanol.
sulfanyl]acetic acid (VIIIc). Yield 62%, mp 127–128°С.
IR spectrum, ν, cm–1: 2980–2560 (СООН), 1690, 1685
1
(С=О). Н NMR spectrum, δ, ppm: 4.04 s (2Н, СН),
7.42 m (2Нarom), 7.58 m (3Нarom), 9.50 s (1Н, СН=О),
12.90 br.s (1Н, СООН). 13C NMR spectrum, δ, ppm:
34.05 (CH2), 127.08, 129.33, 129.93, 134.15 (CAr),
127.14 (C5), 139.97 (C4), 150.23 (C2), 168.90 (COOH),
175.77 (C=O). Found, %: C 48.40; H 2.91; N 9.29.
С12H9ClN2O3S. Calculated, %: C 48.57; H 3.06; N 9.44.
1-Phenyl-2-phenoxy-4-chloro-1H-imidazole-5-
carbaldehyde (VIIf). Yield 75%, mp 85–87°С. IR spec-
trum, ν, cm–1: 1685 (С=О). 1Н NMR spectrum, δ, ppm:
7.27–7.52 m (10Нarom), 9.57 s (1Н, СН=О). 13C NMR
spectrum, δ, ppm: 120.00, 125.92, 127.21, 128.98,
129.22, 129.78, 132.90, 137.63 (CAr), 122.85 (C5), 151.64
(C4), 152.97 (C2), 175.97 (CH=O). Found, %: C 64.57;
H 3.65; N 9.19. [M + 1]+ 299.0. С16H11ClN2O2. Calcu-
lated, %: C 64.33; H 3.71; N 9.38. M 298.7.
1-Phenyl-2-[(4-chlorophenyl)sulfanyl]-4-chloro-
1H-imidazole-5-carbaldehyde (VIIId). Yield 74%, mp
1
90–93°С. IR spectrum, ν, cm–1: 1680 (С=О). Н NMR
spectrum, δ, ppm: 7.45–7.57 m (9Нarom), 9.53 s (1Н,
СН=О). 13C NMR spectrum, δ, ppm:127.46, 129.28,
129.46, 129.98, 132.76, 133.40, 133.94, 134.18 (CAr),
128.96 (C5), 139.30 (C4), 147.12 (C2), 176.48 (CH=O).
Found, %: C 55.29; H 2.94; N 8.17. С16H10Cl2N2OS.
Calculated, %: C 55.03; H 2.89; N 8.02.
1-(4-Methoxyphenyl)-2-(4-tolyloxy)-4-chloro-
1H-imidazole-5-carbaldehyde (VIIg). Yield 70%,
mp 114–115°С. IR spectrum, ν, cm–1: 1685 (С=О).
1Н NMR spectrum, δ, ppm: 2.35 s (3Н, СН3), 7.04 d
(2Нarom, J 9.0 Hz), 7.15 d (2Нarom, J 8.5 Hz), 7.22 d
(2Нarom, J 8.5 Hz), 7.45 (2Нarom, J 9.0 Hz), 9.55 s
(1Н, СН=О). Found, %: C 62.86; H 4.33; N 8.34. [M +
1]+ 343. С18H15ClN2O2. Calculated, %: C 63.07; H 4.41;
N 8.17. M 342.8.
1-Aryl-2-cycloalkylamino-4-chloro-1H-imidazole-
5-carbaldehydes IXа–IXc. To a solution of 0.02 mol of
amine Vа–Vc in 10 ml of ethanol was added 0.005 mol
of aldehyde IIa, IId, or IIf, and the mixture was boiled
for 6 h. The reaction mixture was cooled, diluted with
10 ml of 5% solution of NаОН, and was left overnight.
The obtained precipitate was filtered off, washed with
water, and crystallized from aqueous ethanol.
1-Alkyl(aryl)-2-alkyl(aryl)sulfanyl-4-chloro-1H-
imidazole-5-carbaldehydes VIIIа–VIIId. To a solution
of 5.1 mmol of thiol IVа–IVc in 10 ml of ethanol while
stirring was added in succession 0.2 g (5.1 mmol) of
sodium hydroxide, 5 mmol of aldehyde IIb or IIb, and
the mixture was heated on a boiling water bath for 3 h.
The solvent was evaporated at a reduced pressure, the
residue was diluted with 50 ml of water, the obtained
precipitate was filtered off, dried, and crystallized from
aqueous ethanol.
2-Morpholinyl-1-phenyl-4-chloro-1H-imidazole-
5-carbaldehyde (IXа). Yield 72%, mp 115–117°С. IR
1
spectrum, ν, cm–1: 1685 (С=О). Н NMR spectrum, δ,
ppm: 3.01–3.46 m (8Н, CH2), 7.44–7.50 m (5Нarom),
9.39 s (1Н, СН=О). 13C NMR spectrum, δ, ppm: 123.18
(C5), 127.61, 129.24, 129.36, 135.41 (CAr), 140.71 (C4),
153.11 (C2), 174.47 (CH=O). Found, %: С 57.39; H 4.77;
N 14.26. [M + 1]+ 292. С14H14ClN3О2. Calculated, %:
С 57.64; H 4.84; N 14.40. M 291.4.
1-Methyl-2-[(4-chlorophenyl)sulfanyl]-4-chloro-
1H-imidazole-5-carbaldehyde (VIIIа). Yield 69%, mp
2-Piperidinyl-1-(4-chlorophenyl)-4-chloro-1H-im-
idazole-5-carbaldehyde (IXb).Yield 67%, mp 87–90°С.
IR spectrum, ν, cm–1: 1680 (С=О). 1Н NMR spectrum,
δ, ppm: 1.40–1.54 m (6Н), 3.03–3.08 m (4Н), 7.43 d
(2Нarom, J 7.2 Hz), 7.52 d (2Нarom, J 7.2 Hz), 9.36 s (1Н,
СН=О). 13C NMR spectrum, δ, ppm: 23.21 (CH2), 24.27
(CH2), 48.66 (CH2), 122.80 (C5), 129.10, 129.51, 133.48,
134.94 (CAr), 141.85 (C4), 153.90 (C2), 175.99 (CH=O).
Found, %: С 55.44; H 4.60; N 12.84. С15H15Cl2N3О.
Calculated, %: С 55.57; H 4.66; N 12.96.
1
67–70°С. IR spectrum, ν, cm–1: 1685 (С=О). Н NMR
spectrum, δ, ppm: 3.88 s (3Н, СН3), 7.45 m (4Нarom),
9.70 s (1Н, СН=О). Found, %: C 46.27; H 2.75; N 9.61.
С11H8Cl2N2OS. Calculated, %: C 46.01; H 2.81; N 9.76.
1-Phenyl-2-cyclohexylsulfanyl-4-chloro-1H-imid-
azole-5-carbaldehyde (VIIIb).Yield 61%, mp 95–97°С.
IR spectrum, ν, cm–1: 1685 (С=О). 1Н NMR spectrum,
δ, ppm: 1.13–2.04 m (10Н, СН2), 3.77 br.s (1Н, СН),
7.34–7.56 m (5Нarom), 9.50 s (1Н, СН=О). Found, %:
C 60.15; H 5.39; N 8.59. С16H17ClN2OS. Calculated, %:
C 59.9; H 5.34; N 8.73.
4-Chloro-2-[3,4-dihydro-2(1H)-isoquinolinyl]-1-(4-
methylphenyl)-1H-imidazole-5-carbaldehyde (IXc).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

POLYFUNCTIONAL IMIDAZOLES: ІІ.
709
Yield 64%, mp 104–105°С. IR spectrum, ν, cm–1: 1685
(С=О). Н NMR spectrum, δ, ppm: 2.44 s (3Н, СН3),
2. Chien, T-Ch., Saluya, S.S., Drach, D.C., and Towsend, L.B.,
J. Med. Chem., 2004, vol. 47, p. 5443.
1
3. Tomioka, H., Yano, T., Takada, X., Takeda, H., and
Hirata, N., Agricul. Biol. Chem., 1991, vol. 55, p. 1601.
4. Almansa, C., Alfon, J., de, Arrida, A.F., Cavalcanti, F.L.,
Escamilla, J., Gomes, L.A., Miralles, A., Soliva, R.,
Bartroli, J., Carseller, E., Merlos, M., and Garcia-
Bofanell, J., J. Med. Chem., 2003, vol. 46, p. 3463.
5. Byuttel’mann, B., Chekarelli, S.M., Ieshke, G., Porter, R.
Kh.F., Fiaira, E., Kol’chevski, Z., EA Patent 010577,
vol. 1, 2008; http: www.eapo.org/rus/bulletin/ea200805/
HTML/010577.html.
6. Mjalli,A., Europe Inventor’s Certificate 2082740A2, 2009;
http://ep.espacenet.com
7. Sugimoto, H. and Fujiwara, T., US Patent 6147097, 2000;
http://patft.uspto.gov/
8. Dumeunier, R., Lamberth, C., Trah, S., and Wendeborn, S.,
WO Inventor’s Certidicate 053102, 2009; http://
ep.espacenet.com/
9. Dumeunier, R., Lamberth, C., and Trah, S., WO Inventor’s
Certidicate 127615, 2009; http://ep.espacenet.com/
10. Albuquerque, J.F.C., Rolea, Filho, J.A., Brandao, S.S.T.,
Lima, M.C.A., Ximenes, E.A., Galdino, S.L., Pitta, I.R.,
Chantegrel, J., Perrisin, M., and Luu-Duc, C., Farmaco,
1999, vol. 54, p. 77.
2.63 t (2Н, СН2, J 6.0 Hz), 3.29 d (2Н, СН2, J 6.0 Hz),
4.37 s (2Н, СН2), 7.01–7.13 m (4Нarom), 7.34 m (4Нarom),
9.38 s (1Н, СН=О). Found, %: С 68.06; H 5.03; N 11.79.
С20H18ClN3О. Calculated, %: С 68.28; H 5.16; N 11.94.
1-Aryl-2,4-dichloro-1Н-imidazole-5-carbaldehyde
imines XIа–XId. To a solution of 0.015 mol of amine in
10 ml of ethanol was added 1.2 g (0.005 mol) of aldehyde
IIb, IId, or IIg, and the mixture was stirred at room tem-
perature for 12 h. The reaction mixture was diluted with
10 ml of water, and the obtained precipitate was filtered
off and crystallized from aqueous ethanol.
N-[(2,4-Dichloro-1-phenyl-1H-imidazol-5-yl)-
methylene]-N-methylamine (XIа). Yield 84%, mp
110–111°С. IR spectrum, ν, cm–1: 1665 (С=N). 1Н NMR
spectrum, δ, ppm: 3.20 s (3Н, СН3), 7.40 m (2Нarom),
7.55 m (3Нarom), 7.95 s (1Н, СН=N). 13C NMR spectrum,
δ, ppm: 48.3 (CH3), 126.16, 127.90, 129.35, 129.87 (CAr),
129.77 (C5), 133.00 (C2), 134.23 (C4), 148.58 (CH=N).
Found, %: С 51.78; H 3.48; N 16.47. С11H9Cl2N3. Cal-
culated, %: С 51.99; H 3.57; N 16.54.
2-({[2,4-Dichloro-1-(4-chlorophenyl)-1H-imidazol-
5-yl]methylene}amino)ethanol (XIb). Yield 71%, mp
120–121°С. IR spectrum, ν, cm–1: 1665 (С=N). 1Н NMR
spectrum, δ, ppm: 3.27–3.45 m (4Н, Н2), 4.43 br.s (1Н,
ОН), 7.34–7.61 m (4Нarom), 7.94 s (1Н, СН=N). Found,
%: С 45.29; H 3.23; N 13.10. С12H10Cl3N3О. Calculated,
%: С 45.24; H 3.16; N 13.19.
11. Kochkanyan, V.O., Israelyan, Yu.A., and Zaritovskii, A.I.,
Khim. Geterotsikl. Soedin., 1978, p. 87.
12. Beckurts, Y., Frerich, G., and Beckurts, H., Arch. Pharm.,
1899, vol. 237, p. 331.
13. Baranov, S.I., Kochkanyan, R.O., Zaritovskii, A.I.,
Belova, G.I., and Radnova, S.S., Khim. Geterotsikl.
Soedin., 1975, p. 85.
14. Iddon, B. and Khan, N., Tetrahedron Lett., 1986, vol. 27,
p. 1635.
15. Eriksen, B.L., Vedso, P., and Begtrup, M., J. Org. Chem.,
2001, vol. 66, p. 8344.
16. Chemical Reactivity and Reaction Paths, Klopman, G.,
Ed., New York: Wiley, 1974.
17. Gaussian 98W (Revision, A.7), Pittsburgh: Gaussian, Inc.,
1998. www.gaussian.com/
N-[(2,4-Dichloro-1-phenyl-1H-imidazol-5-yl)-
methylene]-N-phenylamine (XIc). Yield 76%, mp
1
72–75°С. IR spectrum, ν, cm–1: 1670 (С=N). Н NMR
spectrum, δ, ppm: 6.95–7.55 m (10Нarom), 8.15 s
(1Н, СН=N). Found, %: С 60.99; H 3.34; N 13.15.
С16H11Cl2N3. Calculated, %: С 60.78; H 3.51; N 13.29.
N-{[2,4-Dichloro-1-(4-methoxyphenyl)-1H-imidaz-
ol-5-yl]methylene}-N-(4-methylphenyl)amine (XId).
Yield 74%, mp 66–67°С. IR spectrum, ν, cm–1: 1670
18. Foster, J.P. and Weinhold, F., J. Am. Chem. Soc., 1980,
vol. 102, p. 7211.
19. Besler, B.H., Merz, K.M., and Kollman, P.A., J. Comp.
Chem., 1989, vol. 11, p. 431.
20. Singh, U.C. and Kollman, P.A., J. Comp. Chem., 1984,
vol. 5, p. 129.
21. Sykes, P., A Guidebook to Mechanism in Organic
Chemistry, 2nd edn., London: Longmans, 1966.
22. Sheldrikc, G.M., SHELXS97. Program for Solution of
Crystal Structure, University of Gtsttingen, Germany,
1997.
1
(С=N). Н NMR spectrum, δ, ppm: 2.36 s (3Н, СН3),
3.83 s (3Н, СН3О), 6.90 d (2Нarom, J 7.8 Hz), 7.03–4.21 m
(4Нarom), 7.49 d (2Нarom, J 7.8 Hz), 8.89 s (1Н, СН=N).
Found, %: С 60.09; H 4.23; N 11.60. С18H15Cl2N3О.
Calculated, %: С 60.01; H 4.20; N 11.66.
REFERENCES
23. Sheldrik, G.M., SHELXS97. Program for the Refinement
of Crystal Structures, Univetsity of Gtsttingen, Germany,
1997.
1. Chornous, V.A., Bratenko, M.K., and Vovk, M.V., Zh. Org.
Khim., 2009, vol. 45, p. 1219.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011