Ambidentate properties of asymmetric substituted imidazoles. Direction of benzylation of 2-[N-(4-chlorophenyl)carbamoyl]methylthio-4-phenyl-1H-imidazole

Article abstract of DOI:10.1007/s10593-005-0217-1

On the basis of ¹H-¹H two dimensional NMR spectroscopy (NOESY) it has been unambiguously shown that the benzylation of 2-[N-(4-chlorophenyl)carbamoyl]methylthio-4-phenyl-1H-imidazole occurs at the N₍₁₎ atom. This data was

Full text of DOI:10.1007/s10593-005-0217-1

Chemistry of Heterocyclic Compounds, Vol. 41, No. 6, 2005
AMBIDENTATE PROPERTIES OF ASYMMETRIC
SUBSTITUTED IMIDAZOLES. DIRECTION OF
BENZYLATION OF 2-[N-(4-CHLOROPHENYL)-
CARBAMOYL]METHYLTHIO-4-PHENYL-1H-IMIDAZOLE
A. G. Ivanova, R. V. Kombarov, P. V. Davidenko, and O. G. Rodin
1
On the basis of H-1H two dimensional NMR spectroscopy (NOESY) it has been unambiguously shown
that the benzylation of 2-[N-(4-chlorophenyl)carbamoyl]methylthio-4-phenyl-1H-imidazole occurs at the
N(1) atom. This data was confirmed by comparison of the properties of the alkylation product obtained
with the corresponding N(3)-benzylimidazole isomer synthesized independently.
1
Keywords: imidazole-2-thiols, asymmetric substituted imidazoles, benzylation, H-1H two dimensional
NMR spectroscopy (NOESY).
4-Arylimidazolyl-2-thione derivatives show a broad spectrum of biological activity [1, 2]. Hence
alkylation of 4-arylimidazolyl-2-thiones by reagents having a mobile halogen atom and under mild conditions
forms the corresponding sulfide derivatives [1, 2], many of which are immunomodulatory, antitumor, and
antihypertensive agents [3-8]. However, despite quite an amount of data reported in the literature regarding the
S-alkylation of mercaptoimidazoles, comparatively few reliable publications concern the direction of
N-alkylation of the imidazole ring.
The formation of two regioisomers is theoretically possible for the alkylation of asymmetric substituted
imidazoles.
R1
N
N
N
HalR1
+
R
R
R
NaHCO3 (K2CO3)
Ph
S
Ph
S
Ph
S
N
N
N
H
R1
We present evidence for the direction of benzylation of the model compound 2-[N-(4-chlorophenyl)-
carbamoyl]methylthio-4-phenyl-1H-imidazole (1) on the basis of two dimensional 1H-1H NMR spectroscopy and
the independent synthesis of a strictly fixed isomer.
The following consecutive reactions have been used to synthesize the sulfide 1. Initial
cyclocondensation of α-aminoacetophenone hydrochloride with potassium thiocyanate in the presence of
potassium acetate gave 2-mercapto-4-phenylimidazole which was then alkylated at the sulfur atom by
N-(4-chlorophenyl)chloroacetamide to give the sulfide 1. Sulfide 1 was then alkylated by benzyl chloride in
DMF in the presence of excess potassium carbonate.
__________________________________________________________________________________________
ASINEX, Moscow 123182, e-mail: RKombarov@asinex.com. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 882-886, June, 2005. Original article submitted March 11, 2003.
0009-3122/05/4106-0761©2005 Springer Science+Business Media, Inc.
761

H
N
Cl
H
O
O
N
Cl
KNCS
_
+
NH3 Cl
SH
Ph
NaOH
Ph
MeCOOK
Ph
N
H
N
H
Cl
N
S
K2CO3
DMF
Ph
N
O
Cl
1
H
H
A
H
1
N
H
5
2
N
4
S
N
C
B
3
O
Cl
2
TLC data for the reaction mixture showed the formation of a single benzylation product, the structure of
which was shown to be compound 2 from 1H NMR spectroscopic and mass spectrometric data.
1
Physicochemical and spectroscopic characteristics for the compound prepared (Rf, mp, H NMR
chemical shifts) were compared with the constants for compound 3 prepared by an independent route.
N
O
_
MeCO2K
+
Ph
SH
NCS
+ Ph
NH3 Cl
N
Ph
Ph
3
H
o-
H
4
N
N
H
Cl
2
N
1
N
O
S
5
B
C
Cl
O
Cl
NaOH
o-H
H
A
H
3
In this case the starting compound for formation of the imidazole ring in the condensation with
α-aminoacetophenone was N-benzylisothiocyanate which gave 1-benzyl-2-mercapto-5-phenyl-1H-imidazole
[9]. Alkylation at the sulfur atom using N-(4-chlorophenyl)chloroacetamide gives 1-benzyl-2-[N-(4-
chlorophenyl)carbamoyl]methylthio-5-phenyl-1H-imidazole (3).
It was found that the Rf, melting point, and solubility of compound 2 differ markedly from the
1
corresponding values for compound 3. In the H NMR spectra the signal for the imidazole H-5 proton in
compound 2 was shifted by about 0.4 ppm to lower field when compared with the signal of the analogous proton
for compound 3 as a result of the deshielding effect of the aromatic ring A and is thus indirect evidence for the
structure of compound 2 proposed by us.
However, the final proof that the benzylation of sulfide 1 is really at the N(1) atom of the imidazole ring
was obtained by a comparison of the two dimensional 1H-1H NMR (NOESY) spectra of compounds 2 and 3.
762

Fig. 1. 2D 1H-1H NOESY NMR Spectrum of Compound 2.
Fig. 2. 2D 1H-1H NOESY NMR Spectrum of Compound 3.
763

1
The 2D H-1H NOESY NMR spectrum of compound 2 (Fig. 1) shows cross peak I which reflects the
interaction of the benzyl CH2 group protons with the imidazole H-5 proton in compound 2. In contrast to
compound 3 these are closely related sterically.
1
The 2D H-1H NOESY spectrum of compound 3 (Fig. 2) shows cross peak II and this reflects the
interaction of the benzyl CH2 group protons with the o-H protons of benzene ring B. In contrast to compound 2
these are closely related sterically.
This data unambiguously confirms the structure of isomer 2 and thus the benzylation of the sulfide 1 at
the less sterically hindered nitrogen atom of the imidazole ring.
EXPERIMENTAL
1
1H NMR spectra were recorded on a Bruker MSL-300 (300 MHz) instrument and 2D H-1H NOESY
NMR spectra on a Bruker DRX-500 (500 MHz) instrument using DMSO-d6 and TMS internal standard. Mass
spectrometric analysis was carried out on a Thermo Finnigan Surveyor MSQ instrument in the electrospray
injection mode and positive ions were recorded at 500°C with a needle tip voltage of 3 kV. TLC was carried out
in chloroform–methanol (50:1) on Sorbfil plates.
2-[N-(4-Chlorophenyl)carbamoyl]methylthio-4-phenyl-1H-imidazole (1). A 5% aqueous solution of
NaOH (8.8 ml, 11 mmol) and N-(4-chlorophenyl)chloroacetamide (2.24 g, 11 mmol) were added to a suspension
of 2-mercapto-4-phenyl-1H-imidazole (1.64 g, 10 mmol) in 2-propanol (30 ml) with heating and refluxed for
20 min to the finish of the reaction (TLC monitoring). The white precipitate was filtered off and washed with
water and 2-propanol to give compound 1 (2.41 g, 70%); mp 181-182°C, Rf 0.25. Found, %: C 59.05; H 4.48;
N 12.03. [M+1] 386.87. C18H17ClNO3S. Calculated, %: C 59.39; H 4.08; N 12.23. [M+1] 386.87.
2-[N-(4-Chlorophenyl)carbamoyl]methylthio-1-benzyl-4-phenyl-1H-imidazole
(2).
Potassium
carbonate (0.207 g, 1.5 mmol) and benzyl chloride (0.151 g, 1.2 mmol) were added to a solution of the sulfide 1
(0.343 g, 1 mmol) in DMF (2 ml) and refluxed for 10 min with vigorous stirring. The cooled reaction mixture
was treated with water (3 ml). The crystals formed were filtered, washed with water, and recrystallized from
2-propanol to give compound 2 (0.23 g, 53%); mp 129-130°C, Rf 0.84. 1H NMR spectrum, δ, ppm (J, Hz): 4.00
(2H, s, S–CH2); 5.30 (2H, s, CH2Ph); 6.93 (2H, d, J = 8, H-3,5, PhC); 7.20 (1H, s, H-5); 7.22-7.38 (10H, m, PhA,
PhB); 7.59 (2H, d, J = 8, H-2,6, PhC); 10.44 (1H, s, NH). Found, %: C 66.52; H 4.54; N 9.65. [M+1] 434.96.
C24H20ClN3OS. Calculated, %: C 66.43; H 4.65; N 9.68. [M+1] 434.96.
2-[N-(4-Chlorophenyl)carbamoyl]methylthio-1-benzyl-5-phenyl-1H-imidazole (3). A 5% aqueous
solution of NaOH (0.88 ml, 1.1 mmol) and N-(4-chlorophenyl)chloroacetamide (0.224 g, 1.1 mmol) were added
with heating to a suspension of 1-benzyl-2-mercapto-5-phenyl-1H-imidazole [9] (0.254 g, 1 mmol) in
2-propanol (4 ml) and refluxed for 25 min to the finish of the reaction (TLC monitoring). The white precipitate
was filtered off and washed with water and 2-propanol to give compound 3 (0.329 g, 76%); mp 183-184°C,
1
Rf 0.54. H NMR spectrum, δ, ppm (J, Hz): 4.00 (2H, s, S–CH2); 5.25 (2H, s, CH2Ph); 7.18-7.42 (10H, m, PhA,
PhB); 7.58 (2H, d, J = 8, H-3,5, PhC); 7.73 (2H, d, J = 8, H-2,6, PhC); 7.81 (1H, s, H-5); 10.41 (1H, s, NH).
Found, %: C 66.34; H 4.47; N 9.61. [M+1] 434.96. C24H20ClN3OS. Calculated, %: C 66.43; H 4.65; N 9.68.
[M+1] 434.96.
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