SHORT PAPER
New One-step Synthesis of 2-Aryl-1H-Imidazoles
1815
pounds 3a-i). The choice of the substituents was made sion of 2-phenyl-1H-imidazolines 2e-i gave very low
with respect to their position on the phenyl ring, ortho, yields of 3e-i.
meta or para position, as well as to their electronic effects
(Me, Cl, CF3, etc.).
Thanks to our new protocol employing DMSO as a re-
agent, good yields have been obtained for almost all the
Major difficulties concerning the synthesis of 2-trifluo- aromatic derivatives prepared but not for aliphatic com-
romethyl-phenyl-D2-imidazoline did not allow us to pro- pounds. We should conclude that these two methods are
ceed to the preparation of the corresponding imidazole. complementary.
The synthesis of the 2-trifluoromethyl-phenyl-1H-imida-
zole, however, has already been described in the litera-
Mps were determined on a DSC-50 Shimadzu apparatus. IR spectra
ture.11 It was prepared by electrolysis of 2-trifluoro-
were recorded on a Perkin-Elmer 983G spectrophotometer. All
benzoiodide in the presence of imidazole anion in 35%
1H-imidazole compounds present a large interval of IR absorption
yield.11
bands between 2600 cm-1 and 3180 cm-1 (nCH, CH2, CH3, and
nNH). 1H NMR data are in agreement with the literature. The mi-
croanalyses were performed at the Microanalytical Laboratory of
ENSCT in Toulouse and the results obtained are within 0.4% of
the theoretical values. Reactions were monitored by TLC and prod-
uct mixtures were purified by column chromatography using silica
gel 60 F254 (70-200 mesh). The D2-imidazolines 2 were synthe-
sized by addition of an excess of diaminoethane to the correspond-
ing nitriles in the presence of catalytic amounts of phosphorus
pentasulfure.2
The other compounds prepared contain 2-aromatic-1H-
imidazoles (compounds 3j-l), the aliphatic derivative
3m, and the benzyl derivative 3n. The results obtained are
shown in the Table.
Apparently, the position of the substituent on the phenyl
ring, ortho, meta or para position, does not greatly affect
the yield (Table). On the other hand, the yields are rela-
tively sensitive to the electronic effects of each substitu-
ent. For example, with the para derivatives 3d, 3g, and 3i,
the yields considerably decrease in the presence of elec-
Procedure A
A stirred solution of the D2-imidazoline 2 (3 mmol) in DMSO
tro-attractive substituents (Cl, CF3) and become dramati- (5 mL) was heated at 120 °C in an oil bath for 48 h. After cooling,
either H2O was added (8 mL) and the crude 1H-imidazole 3 was col-
cally low in the case of the trifluoromethyl group 3i.
lected by filtration, or the crude mixture was poured into H2O
Both Pd/C and DMSO gave good overall yields of pure
(50 mL) and extracted with CH2Cl2 (3 ¥ 100 mL). The organic layer
materials for the three methyl analogs prepared 3b-d.
However, for compounds 3e-i, DMSO performed nota-
bly better.
was then dried (MgSO4) and the solvent was removed under re-
duced pressure. Finally, the residue was subjected to column chro-
matography (CH2Cl2/EtOAc, 1:1).
The syntheses of the 2-(2-naphthyl)- and the 2-(2-benzo-
furanyl)-1H-imidazoles, 3j-k, were successful and inde-
pendent of the choice of the reagent (DMSO or Pd/C).
However, the results achieved by DMSO were better than
those obtained in the presence of Pd/C.
Procedure B
A suspension of 10% Pd/C (0.50 g) and D2-imidazoline 2 (0.50 g)
in toluene (25 mL) was refluxed in an oil bath for 48 h. After cool-
ing, the Pd/C was removed by filtration. The organic layer was con-
centrated in vacuo to give a crude residue, imidazole 3, which was
purified by column chromatography according to procedure A.
The conversion of the 2-(4-tolyl)-4-methyl-D2-imidazo-
line 2l to the corresponding 1H-imidazole 3l was better in
the presence of DMSO (75% yield). Pd/C was a poor re-
agent affording only 10% yield.
Acknowledgement
The authors thank the “Laboratoires SERVIER” for their support
and more particularly Mr. D. H. Caignard and Mr. P. Renard. The
authors also thank Laurent Amielet and Christelle Recoche for tech-
nical support.
Unfortunately, the oxidation of 2-aliphatic and 2-benzyl
imidazolines (compounds 3m-n) with DMSO was unsuc-
cessful. Therefore, for the synthesis of the benzyl analog
3n, the use of Pd/C was absolutely necessary.
References
Both DMSO and Pd/C use mild experimental conditions,
120 °C, for the same reaction time, 48 hours. Neither de-
mands the presence of any other reagent and they do not
produce any side products. DMSO being completely mis-
cible with water allows an easy recovery of the product,
either by precipitation or by extraction (procedure A).
Similarly Pd/C is easily removed by filtration although it
is more expensive and more of a pollutant than DMSO
(procedure B).
(1) New address: Université Paris-Sud, Unité de Chimie
Organique Associée au CNRS, Faculté de Pharmacie, Tour
D3, 3ème étage. 5, rue J.-B. Clément, 92296 Châtenay-
Malabry, France.
E-mail: maria.anastassiadou@pro.worldonline.fr
(2) Anastassiadou, M.; Danoun, S.; Crane, L.; Baziard-Mouysset,
G.; Payard, M.; Caignard, D. -H.; Renard, P.; Rettori, M. -C.
Bioorg. Med. Chem. 2000, (accepted for publication).
Corbel, J. C.; Uriac, P.; Huet, J.; Martin, C. A. E.; Advenier,
C. Eur. J. Med. Chem. 1995, 3.
Among the important number of methods describing the
dehydrogenation of D2-imidazolines to 1H-imidazoles,
Pd/C seems to be one of the few reagents giving good re-
sults for products with different physical and structural
properties. However, employment of Pd/C for the conver-
Doyle, T. J.; Haseltine, J. J. Heterocycl. Chem. 1994, 1417.
Helgen, L.; Stoutland, O.; Courtland, L. A. J. Org. Chem.
1959, 884.
(3) Dockner, T.; Frank, A. Ger. Offen. 1979, 2,729,017.
(4) Kyrudes, L. P.; Zienty, F. B.; Steahly, G. W.; Morrill, H. L. J.
Org. Chem. 1947, 577.
Synthesis 2000, No. 13, 1814–1816 ISSN 0039-7881 © Thieme Stuttgart · New York
Anastassiadou
