Polyfunctional imidazoles: VII.* 1-aryl-4-chloro-5-[hydroxy(halo) methyl]-1H-imidazoles and their derivatives

Article abstract of DOI:10.1134/S1070428013040131

The reduction of 1-aryl-4-chloro-1H-imidazole-5-carbaldehydes with sodium tetrahydridoborate gave 1-aryl-4-chloro-1H-imidazol-5-ylmethanols which were converted into 5-chloromethyl and 5-fluoromethyl derivatives. 1-Aryl-4-chloro-5-chloromethyl-1H-imidazol

Full text of DOI:10.1134/S1070428013040131

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 4, pp. 568–574. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.A. Chornous, A.N. Grozav, D.V. Klyukovskii, A.V. Bezdudnyi, M.V. Vovk, 2013, published in Zhurnal Organicheskoi Khimii, 2013,
Vol. 49, No. 4, pp. 585–590.
Polyfunctional Imidazoles:
VII.* 1-Aryl-4-chloro-5-[hydroxy(halo)methyl]-1H-imidazoles
and Their Derivatives
V. A. Chornousa, A. N. Grozava, D. V. Klyukovskiib, A. V. Bezdudnyib, and M. V. Vovkb
a Bukovina State Medical University, Teatral’naya pl. 2, Chernovtsy, 58000 Ukraine
e-mail: chornous@inbox.ru
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
Received July 7, 2012
Abstract—The reduction of 1-aryl-4-chloro-1H-imidazole-5-carbaldehydes with sodium tetrahydridoborate
gave 1-aryl-4-chloro-1H-imidazol-5-ylmethanols which were converted into 5-chloromethyl and 5-fluoro-
methyl derivatives. 1-Aryl-4-chloro-5-chloromethyl-1H-imidazoles reacted with sodium azide, secondary
amines, thiols, and triphenylphosphine to produce the corresponding products of chlorine replacement in the
5-chloromethyl group.
DOI: 10.1134/S1070428013040131
Extensive development of the chemistry of poly-
functional imidazoles during the past two decades has
been determined to some extent by the discovery of
nonpeptide angiotensine II receptor blockers among
2-butyl-4-chloroimidazoles with a functionalized
methyl group in the 5-position [2–6]. These studies led
to the creation of Losartan, a highly efficient drug for
the treatment of arterial hypertension [7, 8].
thetic purposes, e.g., for the design of biologically
active compounds. Of specific interest are new 5-[hy-
droxy(chloro)methyl]imidazoles which are the subjects
of the present study.
1-Benzyl- and 1-(diphenylmethyl)-4-chloro-5-(hy-
droxymethyl)imidazoles are generally synthesized by
benzylation [3, 5, 9] or diphenylmethylation [4, 6] of
the corresponding 1-unsubstituted imidazoles. Aryla-
tion of N1H imidazoles was carried out only with the
use of 1-fluoro-4-nitrobenzene [10, 11], and this reac-
tion has not been further developed. We now propose
to synthesize 1-aryl-5-(hydroxymethyl)imidazoles by
reduction of previously prepared 1-aryl-4-chloro-1H-
imidazole-5-carbaldehydes Ia–Ih [12, 13] with sodium
tetrahydridoborate in boiling ethanol. In this way,
5-hydroxymethyl derivatives IIa–IIh were obtained in
high yield (Scheme 1).
Cl
N
Me
OH
N
NH
N
N
N
Losartan
Scheme 1.
Cl
Cl
However, simpler representatives of 4-chloro-5-
(X-methyl)imidazoles, in particular those having no
substituent in the 2-position or chlorine-substituted, as
well as those containing simple aromatic substituents
on N1, still remain unknown, though such compounds
may be versatile building blocks convenient for syn-
N
N
NaBH4
OH
R2
CHO
R2
N
R1
N
R1
Ia–Ih
IIa–IIh
R2 = H, R1 = Ph (a), 3-MeC6H4 (b), 4-FC6H4 (c), 4-ClC6H4 (d),
4-MeC6H4 (e); R2 = Cl, R1 = Ph (f), 4-FC6H4 (g), 4-MeC6H4 (h).
* For communication VI, see [1].
568

POLYFUNCTIONAL IMIDAZOLES: VII.
569
The hydroxy group in II was successfully replaced
by halogen. By heating alcohols IIa and IIc–IIh with
excess thionyl chloride in boiling toluene we obtained
72–78% of 5-chloromethyl derivatives IIIa–IIIg.
Treatment of imidazoles IIa, IIb, IId, IIg, and IIh
with 4-(trifluoro-λ4-sulfanyl)morpholine [14] afforded
5-fluoromethyl derivatives IVa–IVe (Scheme 2) whose
structural analogs are selective CB1 cannabinoid
receptor antagonists [15].
pounds IIIc, IIIe, and IIIf reacted with excess sodium
azide in DMF at room temperature to afford 5-(azido-
methyl)imidazoles Va–Vc. The reaction of 5-(chloro-
methyl)imidazoles IIIa, IIIc, IIIe, and IIIh with
excess morpholine, piperidine, and dimethylamine at
room temperature or on heating in acetonitrile gave
5-aminomethyl derivatives VIa–VId. Sulfides VIIa–
VIIe were obtained by reaction of imidazoles IIIb–
IIIe and IIIg with 3 equiv of 4-chlorobenzenethiol,
4-hydroxy-6-methylpyrimidine-2(1H)-thione, and
1,3-benzothiazole-2(3H)-thione at 90°C in DMF. The
alkylation of triphenylphosphine with 5-(chloro-
methyl)imidazoles IIIa, IIIc, IIIe, and IIIf in boiling
benzene resulted in the formation of phosphonium
salts VIIIa–VIIId (Scheme 3).
Scheme 2.
Cl
N
SOCl2
Cl
R2
N
R1
The structure of imidazoles V–VIII was confirmed
by the chemical shifts of the 5-CH2 protons in their
1H NMR spectra. The corresponding protons in initial
chloromethyl derivatives III resonated at δ 4.34–
4.49 ppm. Replacement of the chlorine atom in the
chloromethyl group by azido- and sulfanyl groups with
similar electron-acceptor power insignificantly changed
the position of the 5-CH2 signals. Electron-donating
amino groups in VIa–VId induced upfield shift of the
methylene proton signal (δ 3.16–3.28 ppm), whereas
downfield shift to δ 4.98–5.25 ppm was observed for
compounds VIIIa–VIIId where the methylene group
was attached to acceptor phosphonium moiety.
IIIa–IIIg
IIa–IIh
SF3
N
Cl
O
N
F
R2
N
R1
IVa–IVe
III, R2 = H, R1 = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 4-Me-
C6H4 (d); R2 = Cl, R1 = Ph (e), 4-FC6H4 (f), 4-MeC6H4 (g);
IV, R2 = H, R1 = Ph (a), 3-MeC6H4 (b), 4-ClC6H4 (c); R2 =
Cl, R1 = 4-FC6H4 (d), 4-MeC6H4 (e).
Imidazoles III are polyfunctional electrophilic sys-
tems possessing two (IIIa–IIId) or three (IIIe–IIIg)
reaction centers. Study of their behavior toward vari-
ous nitrogen-, sulfur-, and phosphorus-centered nu-
cleophiles showed that these transformations selec-
tively involved only the chloromethyl group. Com-
Comparison of the results obtained in the reactions
of 2,4-dichloro-5-(chloromethyl)imidazoles IIIe, IIIf,
and IIIh with N- and S-nucleophiles with our previous
data [13] on analogous reactions of 2,4-dichloro-
imidazole-5-carbaldehydes shows that the substituent
Scheme 3.
Cl
Cl
HNR32
N
N
NaN3
N3
NR32
R2
R2
N
N
R1
R1
Va–Vc
VIa–VId
IIIa–IIIh
Cl
Cl
R4SH
PPh3
N
N
SR4
PPh3 Cl–
R2
R2
N
N
R1
VIIa–VIIe
R1
VIIIa–VIIId
V, R2 = H, R1 = 4-ClC6H4 (a); R2 = Cl, R1 = Ph (b), 4-FC6H4 (c); VI, R2 = H: R1 = Ph, R32N = morpholin-4-yl (a); R1 = 4-ClC6H4,
R32N = piperidin-1-yl (b); R1 = 4-MeC6H4, R3 = Me (c); R2 = Cl, R1 = Ph, R3 = Me (d); VII, R2 = H, R1 = 4-MeC6H4, R4 =
4-ClC6H4 (a); R1 = 4-ClC6H4, R4 = 4-methyl-6-hydroxypyrimidin-2-yl (b); R1 = 4-FC6H4, R4 = 1,3-benzothiazol-2-yl (c); R2 = Cl:
R1 = Ph, R4 = 4-ClC6H4 (d); R1 = 4-MeC6H4, R4 = 1,3-benzothiazol-2-yl (e); VIII, R2 = H, R1 = Ph (a), 4-ClC6H4 (b); R2 = Cl,
R1 = Ph (c), 4-FC6H4 (d).
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CHORNOUS et al.
570
in position 5 of the imidazole ring deactivates chlorine
atoms in positions 2 and 4 so that they are not replaced
by N- or S-nucleophiles.
4.32 d (2H, CH2, J = 4.8 Hz), 5.30 t (1H, OH, J =
4.8 Hz), 7.40 m (2H, Harom), 7.67 m (2H, Harom), 7.91 s
(1H, 2-H). Found, %: C 53.27; H 3.69; N 12.53.
[M + 1]+ 227. C10H8ClFN2O. Calculated, %: C 53.00;
H 3.56; N 12.36. M 226.64.
EXPERIMENTAL
[4-Chloro-1-(4-chlorophenyl)-1H-imidazol-5-yl]-
methanol (IId). Yield 82%, mp 132–134°C. IR spec-
The IR spectra were recorded in KBr on a UR-20
1
1
trum: ν 3345 cm–1 (OH). H NMR spectrum, δ, ppm:
spectrometer. The H NMR spectra of IIIa–IIIg were
recorded from solutions in CDCl3, and of the other
compounds, in DMSO-d6, and the 13C NMR spectra
were recorded from solutions in DMSO-d6 on a Bruker
Avance DRX-500 instrument at 500.13 and
127.75 MHz, respectively, using tetramethylsilane as
internal reference. The 19F NMR spectra (DMSO-d6)
were measured on a Varian Gemini spectrometer at
188.14 MHz using CCl3F as internal reference. The
mass spectra were obtained on an Agilent 1100/DAD/
HSD/VLG119562 instrument.
(4-Chloro-1H-imidazol-5-yl)methanols IIa–IIh
(general procedure). Sodium tetrahydridoborate,
0.19 g (5 mmol), was added to a solution of 10 mmol
of imidazole-5-carbaldehyde Ia–Ih in 20 ml of etha-
nol, the mixture was heated to the boiling point, and
100 ml of water was added. The precipitate was
filtered off, washed with water, dried, and recrystal-
lized from 80% aqueous ethanol.
4.36 d (2H, CH2, J = 5.0 Hz), 5.35 t (1H, OH, J =
5.0 Hz), 7.65 d (2H, Harom, J = 8.0 Hz), 7.69 d (2H,
H
arom, J = 8.0 Hz), 7.96 s (1H, 2-H). 13C NMR spec-
trum, δC, ppm: 50.58 (CH2), 126.39 (C2), 126.64 (C5);
128.55, 129.44, 130.03, 134.64 (Carom); 136.06 (C4).
Found, %: C 49.65; H 3.43; N 11.70. [M + 1]+ 244.
C10H8Cl2N2O. Calculated, %: C 49.41; H 3.32;
N 11.52. M 243.09.
[4-Chloro-1-(4-methylphenyl)-1H-imidazol-5-
yl]methanol (IIe). Yield 88%, mp 154–156°C. IR
1
spectrum: ν 3340 cm–1 (OH). H NMR spectrum, δ,
ppm: 2.39 s (3H, CH3), 4.33 d (2H, CH2, J = 5.0 Hz),
5.35 t (1H, OH, J = 5.0 Hz), 7.35 d (2H, Harom, J =
7.8 Hz), 7.46 d (2H, Harom, J = 7.8 Hz), 7.84 s (1H,
2-H). Found, %: C 59.08; H 4.90; N 12.70. [M + 1]+
223. C11H11ClN2O. Calculated, %: C 59.33; H 4.98;
N 12.58. M 222.68.
(2,4-Dichloro-1-phenyl-1H-imidazol-5-yl)metha-
nol (IIf). Yield 90%, mp 122–124°C. IR spectrum:
(4-Chloro-1-phenyl-1H-imidazol-5-yl)methanol
(IIa). Yield 85%, mp 158–160°C. IR spectrum:
1
ν 3345 cm–1 (OH). H NMR spectrum, δ, ppm: 4.20 d
1
ν 3350 cm–1 (OH). H NMR spectrum, δ, ppm: 4.36 d
(2H, CH2, J = 5.2 Hz), 5.14 t (1H, OH, J = 5.2 Hz),
7.49–7.61 m (5H, Harom). Found, %: C 49.69; H 3.22;
N 11.35. [M + 1]+ 244. C10H8Cl2N2O. Calculated, %:
C 49.41; H 3.32; N 11.52. M 243.09.
(2H, CH2, J = 5.0 Hz), 5.32 t (1H, OH, J = 5.0 Hz),
7.51–7.63 m (5H, Harom), 7.93 s (1H, 2-H). 13C NMR
spectrum, δC, ppm: 50.67 (CH2), 124.85 (C2), 126.45
(C5); 128.40, 128.56, 129.56, 135.87 (Carom); 135.93
(C4). Found, %: C 57.78; H 4.46; N 13.55. [M + 1]+
209. C10H9ClN2O. Calculated, %: C 57.57; H 4.35;
N 13.43. M 208.65.
[2,4-Dichloro-1-(4-fluorophenyl)-1H-imidazol-5-
yl]methanol (IIg). Yield 80%, mp 135–137°C. IR
1
spectrum: ν 3345 cm–1 (OH). H NMR spectrum, δ,
ppm: 4.19 d (2H, CH2, J = 5.2 Hz), 5.16 t (1H, OH, J =
5.2 Hz), 7.38–7.71 m (4H, Harom). Found, %: C 46.26;
H 2.58; N 10.55. [M + 1]+ 262. C10H7Cl2FN2O. Calcu-
lated, %: C 46.00; H 2.70; N 10.73. M 261.08.
[4-Chloro-1-(3-methylphenyl)-1H-imidazol-5-yl]-
methanol (IIb). Yield 80%, mp 100–102°C. IR spec-
1
trum: ν 3340 cm–1 (OH). H NMR spectrum, δ, ppm:
2.41 s (3H, CH3), 4.36 d (2H, CH2, J = 5.0 Hz), 5.30 t
(1H, OH, J = 5.0 Hz), 7.31–7.46 m (4H, Harom), 7.90 s
(1H, 2-H). 13C NMR spectrum, δC, ppm: 20.84 (CH3),
50.66 (CH2); 121.89, 125.30, 126.43, 129.10, 129.24,
135.87, 139.25 (Carom, C2); 128.52 (C5), 135.82 (C4).
Found, %: C 59.08; H 4.90; N 12.70. [M + 1]+ 223.
C11H11ClN2O. Calculated, %: C 59.33; H 4.98;
N 12.58. M 222.68.
[2,4-Dichloro-1-(4-methylphenyl)-1H-imidazol-
5-yl]methanol (IIh). Yield 89%, mp 128–130°C. IR
1
spectrum: ν 3340 cm–1 (OH). H NMR spectrum, δ,
ppm: 2.41 s (3H, CH3), 4.18 d (2H, CH2, J = 5.0 Hz),
5.11 t (1H, OH, J = 5.0 Hz), 7.36 d (2H, Harom, J =
7.8 Hz), 7.41 d (2H, Harom, J = 7.8 Hz). 13C NMR spec-
trum, δ, ppm: 20.40 (3H, CH3), 51.10 (CH2), 125.89
(C5); 127.32, 129.50, 129.63, 139.53 (Carom); 130.14
(C2), 131.41 (C4). Found, %: C 51.12; H 4.03; N 11.01.
[M + 1]+ 258. C11H10Cl2N2O. Calculated, %: C 51.39;
H 3.92; N 10.90. M 257.12.
[4-Chloro-1-(4-fluorophenyl)-1H-imidazol-5-yl]-
methanol (IIc). Yield 87%, mp 125–127°C. IR spec-
1
trum: ν 3340 cm–1 (OH). H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 4 2013

POLYFUNCTIONAL IMIDAZOLES: VII.
571
1-Aryl-4-chloro-5-chloromethyl-1H-imidazoles
IIIa–IIIg (general procedure). A solution of 1.79 g
(15 mmol) of thionyl chloride was added to a solution
of 5 mmol of alcohol IIa or IIc–IIh in 20 ml of anhy-
drous toluene, and the mixture was heated for 2 h
under reflux. The solvent was evaporated, and the
residue was washed with hexane and dried under
reduced pressure (water-jet pump).
4-Chloro-5-chloromethyl-1-phenyl-1H-imidazole
(IIIa). Yield 72%, mp 60–62°C. 1H NMR spectrum, δ,
ppm: 4.49 s (2H, CH2), 7.24–7.52 m (5H, Harom), 7.59 s
(1H, 2-H). Found, %: C 52.68; H 3.46; N 12.46.
C10H8Cl2N2. Calculated, %: C 52.89; H 3.55; N 12.34.
1-Aryl-4-chloro-5-fluoromethyl-1H-imidazoles
IVa–IVe (general procedure). A solution of 5 mmol of
hydroxymethylimidazole IIa, IIb, IId, IIg, or IIh in
50 ml of methylene chloride was cooled to –50°C,
0.5 ml of 4-(trifluoro-λ4-sulfanyl)morpholine was
slowly added under stirring, and the mixture was
allowed to warm up to room temperature, stirred for
12 h, treated with 30 ml of a saturated solution of
sodium hydrogen carbonate, and stirred for 0.5 h more.
The organic phase was separated, washed with water,
dried over anhydrous sodium sulfate, and filtered, the
filtrate was evaporated, and the residue was purified by
chromatography on silica gel using hexane–ethyl
acetate (8:2) as eluent.
4-Chloro-5-chloromethyl-1-(4-fluorophenyl)-1H-
1
4-Chloro-5-fluoromethyl-1-phenyl-1H-imidazole
imidazole (IIIb). Yield 75 %, mp 65–67°C. H NMR
1
(IVa). Yield 55%, mp 139–140°C. H NMR spectrum,
spectrum, δ, ppm: 4.48 s (2H, CH2), 7.19–7.43 m (4H,
δ, ppm: 5.23 d (2H, CH2, JHF = 50.0 Hz), 7.49–7.64 m
H
arom), 7.57 s (1H, 2-H). Found, %: C 49.25; H 2.62;
19
(6H, Harom, 2-H). F NMR spectrum: δF –196.48 ppm,
N 11.22. C10H7Cl2FN2. Calculated, %: C 49.01;
H 2.88; N 11.43.
t (FCH2, J = 50.8 Hz). Found, %: C 57.19; H 3.70;
N 13.44. [M + 1]+ 211. C10H8ClFN2. Calculated, %:
C 57.02; H 3.83; N 13.30. M 210.64.
4-Chloro-5-chloromethyl-1-(4-chlorophenyl)-1H-
1
imidazole (IIIc). Yield 76%, mp 98–100°C. H NMR
4-Chloro-5-fluoromethyl-1-(3-methylphenyl)-
1H-imidazole (IVb). Yield 50%, mp 81–82°C.
1H NMR spectrum, δ, ppm: 2.44 s (3H, CH3), 5.23 d
spectrum, δ, ppm: 4.48 s (2H, CH2), 7.24–7.54 m (5H,
H
arom, 2-H). Found, %: C 45.71; H 2.55; N 10.85.
C10H7Cl3N2. Calculated, %: C 45.92; H 2.70; N 10.71.
(2H, CH2, JHF = 50.0 Hz), 7.32–7.64 m (5H, Harom
,
2-H). 19F NMR spectrum: δF –196.50 ppm, t (FCH2,
J = 50.6 Hz). Found, %: C 59.01; H 4.57; N 12.60.
[M + 1]+ 225. C11H10ClFN2. Calculated, %: C 58.81;
H 4.49; N 12.47. M 224.67.
4-Chloro-5-(chloromethyl)-1-(4-methylphenyl)-
1H-imidazole (IIId). Yield 78%, mp 79–80°C.
1H NMR spectrum, δ, ppm: 2.38 s (3H, CH3), 4.48 s
(2H, CH2), 7.29 d (2H, Harom, J = 8.2 Hz), 7.51 d (2H,
H
arom, J = 8.2 Hz), 7.59 s (1H, 2-H). Found, %:
4-Chloro-1-(4-chlorophenyl)-5-fluoromethyl-1H-
C 54.98; H 4.31; N 11.80. C11H10Cl2N2. Calculated, %:
C 54.79; H 4.18; N 11.62.
1
imidazole (IVc). Yield 54%, mp 77–78°C. H NMR
spectrum, δ, ppm: 5.22 d (2H, CH2, JHF = 50.0 Hz),
7.38 d (2H, Harom, J = 8.2 Hz), 7.51 d (2H, Harom, J =
8.2 Hz), 7.60 s (1H, 2-H). 19F NMR spectrum:
δF –196.26 ppm, t (FCH2, J = 50.2 Hz). Found, %:
C 49.27; H 3.00; N 11.58. [M + 1]+ 246. C10H7Cl2FN2.
Calculated, %: C 49.01; H 2.88; N 11.43. M 245.09.
2,4-Dichloro-5-chloromethyl-1-phenyl-1H-imid-
1
azole (IIIe). Yield 75%, mp 96–97°C. H NMR spec-
trum, δ, ppm: 4.36 s (2H, CH2), 7.24–7.55 m (5H,
H
arom). Found, %: C 46.11; H 2.57; N 10.87.
C10H7Cl3N2. Calculated, %: C 45.92; H 2.70; N 10.71.
2,4-Dichloro-5-chloromethyl-1-(4-fluorophenyl)-
1H-imidazole (IIIf). Yield 77%, mp 94–95°C.
1H NMR spectrum, δ, ppm: 4.34 s (2H, CH2), 7.28 m
(2H, Harom), 7.52 m (2H, Harom). Found, %: C 43.20;
H 2.27; N 10.19. C10H6Cl3FN2. Calculated, %:
C 42.97; H 2.16; N 10.02.
2,4-Dichloro-5-fluoromethyl-1-(4-fluorophenyl)-
1H-imidazole (IVd). Yield 49%, viscous oily sub-
1
stance. H NMR spectrum, δ, ppm: 5.07 d (2H, CH2,
JHF = 50.0 Hz), 7.25–7.40 m (4H, Harom). 19F NMR
spectrum: δF –197.35 ppm, t (FCH2, J = 50.4 Hz).
Found, %: C 45.40; H 2.45; N 10.50. [M + 1]+ 264.
C10H6Cl2F2N2. Calculated, %: C 45.66; H 2.30;
N 10.65. M 263.08.
2,4-Dichloro-5-chloromethyl-1-(4-methylphenyl)-
1H-imidazole (IIIg). Yield 78%, viscous oily sub-
1
stance. H NMR spectrum, δ, ppm: 2.45 s (3H, CH3),
2,4-Dichloro-5-fluoromethyl-1-(4-methylphenyl)-
4.37 s (2H, CH2), 7.23 d (2H, Harom, J = 8.4 Hz), 7.55 d
(2H, Harom, J = 8.4 Hz). Found, %: C 48.20; H 3.40;
N 10.38. C11H9Cl3N2. Calculated, %: C 47.95; H 3.29;
N 10.17.
1H-imidazole (IVe). Yield 50%, viscous oily sub-
1
stance. H NMR spectrum, δ, ppm: 2.46 s (3H, CH3),
5.12 d (2H, CH2, JHF = 50.0 Hz), 7.21 d (2H, Harom, J =
7.8 Hz), 7.33 d (2H, Harom, J = 7.8 Hz). 19F NMR spec-
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CHORNOUS et al.
572
trum: δF –198.6 ppm, t (FCH2, J = 49.8 Hz). Found, %:
C 51.25; H 3.40; N 10.65. [M + 1]+ 260. C11H9Cl2FN2.
Calculated, %: C 50.99; H 3.50; N 10.81. M 259.11.
1-[4-Chloro-1-(4-chlorophenyl)-1H-imidazol-5-
ylmethyl]piperidine (VIb). Yield 75%, mp 115–
1
117°C. H NMR spectrum, δ, ppm: 1.34–1.40 m (6H,
CH2), 2.26 s (4H, CH2), 3.28 s (2H, CH2), 7.61 d (2H,
5-Azidomethyl-1-aryl-4-chloro-1H-imidazoles
Va–Vc (general procedure). Sodium azide, 0.49 g
(7.5 mmol), was added to a solution of 2.5 mmol of
5-(chloromethyl)imidazole IIIc, IIIe, or IIIf in 20 ml
of anhydrous DMF. The mixture was stirred for 12 h at
room temperature and poured into 100 ml of water,
and the precipitate was filtered off, dried, and recrys-
tallized from 80% aqueous ethanol.
H
arom, J = 7.2 Hz) 7.75 d (2H, Harom, J = 7.2 Hz), 7.94 s
(1H, 2-H). Found, %: C 58.32; H 5.65; N 13.62.
[M + 1]+ 311. C15H17Cl2N3O. Calculated, %: C 58.08;
H 5.52; N 13.54. M 310.23.
(1-Aryl-4-chloro-1H-imidazol-5-yl)-N,N-dimeth-
ylmethanamines VIc and VId (general procedure).
5-(Chloromethyl)imidazole IIId or IIIe, 2.5 mmol,
was added to 10 ml of a 30% solution of dimethyl-
amine in ethanol, and the mixture was stirred for 10 h
at room temperature. The mixture was poured into
50 ml of water, 10 ml of 5% aqueous sodium hy-
droxide was added, and the precipitate was filtered off,
dried, and recrystallized from 80% aqueous ethanol.
5-Azidomethyl-4-chloro-1-(4-chlorophenyl)-1H-
imidazole (Va). Yield 85%, mp 88–89°C. IR spectrum:
1
ν 2160 cm–1 (N3). H NMR spectrum, δ, ppm: 4.47 s
(2H, CH2), 7.58 d (2H, Harom, J = 8.0 Hz), 7.68 d (2H,
Harom, J = 8.0 Hz), 8.37 s (1H, 2-H). Found, %:
C 44.59; H 2.50; N 26.34. [M + 1]+ 269. C10H7Cl2N5.
Calculated, %: C 44.80; H 2.63; N 26.12. M 268.11.
(4-Chloro-4-methylphenyl-1H-imidazol-5-yl)-
N,N-dimethylmethanamine (VIc). Yield 72%,
5-Azidomethyl-2,4-dichloro-1-phenyl-1H-imid-
azole (Vb). Yield 88%, mp 77–78°C. IR spectrum:
1
mp 66–67°C. H NMR spectrum, δ, ppm: 2.08 s (6H,
CH3), 2.38 s (3H, CH3), 3.26 s (2H, CH2), 7.34 d (2H,
1
ν 2160 cm–1 (N3). H NMR spectrum, δ, ppm: 4.30 s
H
arom, J = 7.6 Hz), 7.53 d (2H, Harom, J = 7.6 Hz),
(2H, CH2), 7.53–7.64 m (5H, Harom). Found, %:
C 45.01; H 2.51; N 26.00. [M + 1]+ 269. C10H7Cl2N5.
Calculated, %: C 44.80; H 2.63; N 26.12. M 268.11.
7.28 s (1H, 2-H). Found, %: C 62.74; H 6.60; N 16.97.
[M + 1]+ 250. C13H16ClN3. Calculated, %: C 62.52;
H 6.46; N 16.83. M 249.75.
5-Azidomethyl-2,4-dichloro-1-(4-fluorophenyl)-
(2,4-Dichloro-1-phenyl-1H-imidazol-5-yl)-N,N-
dimethylmethanamine (VId). Yield 88%, mp 73–
1H-imidazole (Vc). Yield 84%, mp 64°C. IR spec-
1
trum: ν 2165 cm–1 (N3). H NMR spectrum, δ, ppm:
1
74°C. H NMR spectrum, δ, ppm: 1.97 s (6H, CH3),
4.31 s (2H, CH2), 7.41–7.67 m (4H, Harom). Found, %:
C 42.11; H 2.23; N 24.65. [M + 1]+ 286. C10H6Cl2FN5.
Calculated, %: C 41.98; H 2.11; N 24.48. M 285.10.
3.16 s (2H, CH2), 7.50–7.61 m (5H, Harom). Found, %:
C 53.54; H 4.93; N 15.68. [M + 1]+ 271. C12H13Cl2N3.
Calculated, %: C 53.35; H 4.85; N 15.55. M 270.16.
(4-Chloro-1-phenyl-1H-imidazol-5-ylmethyl)-
cycloalkylamines VIa and VIb (general procedure).
5-(Chloromethyl)imidazole IIIa or IIIc, 2.5 mmol,
was dissolved in 20 ml of anhydrous acetonitrile,
0.44 g (5 mmol) of morpholine or 0.43 g (5 mmol) of
piperidine was added, and the mixture was heated for
2 h under reflux. The mixture was evaporated, the
solid residue was dissolved in 10 ml of 30% aqueous
HCl, the solution was filtered, 10 ml of 5% aqueous
sodium hydroxide was added to the filtrate, and the
precipitate was filtered off, washed with water, and
recrystallized from 80% aqueous ethanol.
4-(4-Chloro-1-phenyl-1H-imidazol-5-ylmethyl)-
morpholine (VIa). Yield 85%, mp 93–94°C. 1H NMR
spectrum, δ, ppm: 2.28 br.s (4H, CH2), 3.19 s (2H,
CH2), 3.48 br.s (4H, CH2), 7.49–7.70 m (5H, Harom),
7.94 s (1H, 2-H). Found, %: C 60.30; H 5.93; N 15.31.
[M + 1]+ 278. C14H16ClN3O. Calculated, %: C 60.54;
H 5.81; N 15.13. M 277.76.
1-Aryl-4-chloro-5-(X-sulfanylmethyl)-1H-imid-
azoles VIIa–VIIe (general procedure). 5-(Chloro-
methyl)imidazole IIIb–IIIe or IIIg, 2.5 mmol, was
dissolved in 10 ml of DMF, 0.35 g (2.5 mmol) of
potassium carbonate and 0.36 g (2.5 mmol) of
4-chlorobenzenethiol [or 2.5 mmol of 4-hydroxy-6-
methylpyrimidine-2(1H)-thione or 1,3-benzothiazole-
2(3H)-thione] (in the reactions with IIIb–IIId) or
1.05 g (7.5 mmol) of potassium carbonate and 1.08 g
(7.5 mmol) of 4-chlorobenzenethiol [or 7.5 mmol of
4-hydroxy-6-methylpyrimidine-2(1H)-thione or
1,3-benzothiazole-2(3H)-thione] (in the reactions with
IIIe and IIIg) were added, and the mixture was stirred
for 2 h at 90°C, cooled, and poured into water. The
precipitate was filtered off, washed with 10 ml of 20%
sodium hydrogen carbonate and 20 ml of water, dried,
and recrystallized from 80% aqueous ethanol.
4-Chloro-5-[(4-chlorophenyl)sulfanylmethyl]-1-
(4-methylphenyl)-1H-imidazole (VIIa). Yield 80%,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 4 2013

POLYFUNCTIONAL IMIDAZOLES: VII.
573
1
1
mp 76–77°C. H NMR spectrum, δ, ppm: 2.39 s (3H,
mp >250°C. H NMR spectrum, δ, ppm: 5.13 d (2H,
CH2, JHP = 12.8 Hz), 7.13–7.94 m (21H, Harom, 2-H).
Found, %: C 68.52; H 4.85; N 5.88. [M + 1]+ 490.
C28H23Cl2N2P. Calculated, %: C 68.72; H 4.74; N 5.72.
M 489.39.
CH3), 4.14 s (2H, CH2), 7.22 d (2H, Harom, J = 7.6 Hz),
7.29 d (2H, Harom, J = 7.6 Hz), 7.37 s (4H, Harom),
7.79 s (1H, 2-H). Found, %: C 58.59; H 4.13; N 8.20.
[M + 1]+ 350. C17H14Cl2N2S. Calculated, %: C 58.46;
H 4.04; N 8.02. M 349.28.
[4-Chloro-1-(4-chlorophenyl)-1H-imidazol-5-yl-
methyl]triphenylphosphonium chloride (VIIIb).
2-{[4-Chloro-1-(4-chlorophenyl)-1H-imidazol-5-
1
Yield 80%, mp >250°C. H NMR spectrum, δ, ppm:
ylmethyl]sulfanyl}-6-methylpyrimidin-4-ol (VIIb).
1
5.12 d (2H, CH2, JHP = 12.8 Hz), 7.24–7.95 m (20H,
Yield 82%, mp 215–217°C. H NMR spectrum, δ,
H
arom, 2-H). Found, %: C 64.01; H 4.09; N 5.47.
ppm: 2.11 s (3H, CH3), 4.50 s (2H, CH2), 5.97 s (1H,
[M + 1]+ 524. C28H22Cl3N2P. Calculated, %: C 64.20;
H 4.23; N 5.35. M 523.83.
5′-H), 7.56 d (2H, Harom, J = 7.8 Hz), 7.61 d (2H, Harom
,
J = 7.8 Hz), 7.97 s (1H, 2-H), 12.38 br.s (1H, OH).
Found, %: C 49.27; H 3.40; N 15.10. [M + 1]+ 367.
C15H12Cl2N4OS. Calculated, %: C 49.06; H 3.29;
N 15.26. M 367.26.
(2,4-Dichloro-1-phenyl-1H-imidazol-5-ylmethyl)-
triphenylphosphonium chloride (VIIIc). Yield 82%,
1
mp >250°C. H NMR spectrum, δ, ppm: 4.98 d (2H,
CH2, JHP = 12.8 Hz), 6.98 d (2H, Harom, J = 8.0 Hz),
7.09 d (2H, Harom, J = 8.0 Hz), 7.42–7.89 m (16H,
2-{[4-Chloro-1-(4-fluorophenyl)-1H-imidazol-5-
ylmethyl]sulfanyl}-1,3-benzothiazole (VIIc). Yield
1
H
arom). Found, %: C 64.42; H 4.34; N 5.50. [M + 1]+
73%, mp 115–117°C. H NMR spectrum, δ, ppm:
524. C28H22Cl3N2P. Calculated, %: C 64.20; H 4.23;
4.62 s (2H, CH2), 7.33–7.62 m (6H, Harom), 7.78 d (1H,
N 5.35. M 523.83.
Harom, J = 8.4 Hz), 7.97 s (1H, 2-H), 8.00 d (1H, Harom
,
[2,4-Dichloro-1-(4-fluorophenyl)-1H-imidazol-5-
J = 8.4 Hz). Found, %: C 54.52; H 3.07; N 11.32.
[M + 1]+ 376. C17H11ClFN3S2. Calculated, %: C 54.32;
H 2.95; N 11.18. M 375.88.
ylmethyl]triphenylphosphonium chloride (VIIId).
1
Yield 85%, mp >250°C. H NMR spectrum, δ, ppm:
5.25 d (2H, CH2, JHP = 12.4 Hz), 7.15–7.25 m (4H,
2,4-Dichloro-5-[(4-chlorophenylsulfanyl)-
H
arom), 7.46–7.92 m (5H, Harom). Found, %: C 62.30;
methyl]-1-phenyl-1H-imidazole (VIId). Yield 70%,
H 4.04; N 5.04. [M + 1]+ 542. C28H21Cl3FN2P. Calcu-
lated, %: C 62.07; H 3.91; N 5.17. M 541.82.
1
mp 70–71°C. H NMR spectrum, δ, ppm: 3.99 s (2H,
CH2), 7.24 d (2H, Harom, J = 8.4 Hz), 7.32 d (2Harom
,
J = 8.4 Hz), 7.49–7.58 m (5H, Harom). Found, %:
C 52.20; H 3.13; N 7.42. [M + 1]+ 370. C16H11Cl3N2S.
Calculated, %: C 51.98; H 3.00; N 7.58. M 369.70.
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Harom, J = 8.1 Hz), 7.35–7.41 m (3H, Harom), 7.47 t (1H,
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was added to a solution of 2.5 mmol of 5-(chloro-
methyl)imidazole IIIa, IIIc, IIIe, or IIIf in 10 ml of
anhydrous benzene, the mixture was heated for 2 h
under reflux, and the precipitate was filtered off,
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