Expeditious synthesis of 2-aryl substituted imidazolines and imidazoles

Article abstract of DOI:10.3987/COM-06-10708

A versatile and efficient method for the synthesis of 2-aryl substituted imidazolines and imidazoles bearing a carboxylate group on C-4 is reported. Three different synthetic pathways were explored, compared and optimized. The selected procedure involves condensation of methyl 2,3-diaminopropionate with different imino ethers. The ring closure, monitored by LC-MS analysis, was facilitated by heating at reflux in ethanol leading to increase the rate of cyclization.

Full text of DOI:10.3987/COM-06-10708

HETEROCYCLES, Vol. 68, No. 6, 2006
1149
HETEROCYCLES, Vol. 68, No. 6, 2006, pp. 1149 - 1162. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd February, 2006, Accepted, 10th April, 2006, Published online, 11th April, 2006. COM-06-10708
EXPEDITIOUS
SYNTHESIS
OF
2-ARYL
SUBSTITUTED
IMIDAZOLINES AND IMIDAZOLES
Sylvia Lauwagie, Régis Millet, Jean Pommery, Patrick Depreux*, and
Jean-Pierre Hénichart
Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille 2,
EA2692, 3 rue du Professeur Laguesse, B.P. 83, 59006 Lille, France ; E-mail :
patrick.depreux@pharma.univ-lille2.fr
Abstract - A versatile and efficient method for the synthesis of 2-aryl substituted
imidazolines and imidazoles bearing a carboxylate group on C-4 is reported.
Three different synthetic pathways were explored, compared and optimized. The
selected procedure involves condensation of methyl 2,3-diaminopropionate with
different imino ethers. The ring closure, monitored by LC-MS analysis, was
facilitated by heating at reflux in ethanol leading to increase the rate of
cyclization.
1,3-Oxazole, thiazole and imidazole derivatives are the subjects of intensive research. These heterocycles
mimicking amide bond can be viewed as natural conformationally constrained unusual peptides which
could counteract problems that limit clinical applications1-4 of peptides such as : (i) rapid degradation by
many specific or nonspecific peptidases under physiological conditions ; (ii) conformational flexibility
which allows a peptide to bind to more than one receptor or receptor subtype ; (iii) poor absorption and
transportation. In addition these heterocycles constitute excellent chelating agents able to bind to many
metalloenzymes. A large number of strategies have also employed imidazoline and imidazole to develop
original compounds. For example, these heterocycles were introduced in the design of farnesyl protein
transferase inhibitors such as Zarnestra5 or new efficient non peptidic medicinal compounds.6 Moreover,
the replacement of amino acids by heterocyclic groups has been used in the design of AT1 angiotensin II
antagonists such as Losartan7 or Irbesartan8 and analogues9,10 (Scheme 1).

1150
HETEROCYCLES, Vol. 68, No. 6, 2006
N
N
N
N
Cl
Cl
N
N
O
OH
N
NH2
N
N
N
NH
N
N
N
H
Cl
N
O
Zarnestra
Losartan
Irbesartan
Scheme 1
Thus, we planned to incorporate imidazole and imidazoline rings for the design of new anticancer agents.
Our goal is to develop an efficient and hydrolyse-resistant analogues of anandamide, an endogenous lipid
which acts as a cannabinoid receptor ligand and has potent anticarcinogenic activities in several cancer
cell types.11-14 Then, to design such cannabimimetic compounds, we have developed and optimized
methods for the preparation of various imidazoline and imidazole derivatives. These compounds include
different biaryl-type structures and a 5-membered heterocycle, mimicking the arachidonic chain of
anandamide15 and the amide function of anandamide, respectively16 (Scheme 2).
In this paper we report the preparation of biarylimidazolines and imidazoles bearing a carboxylate group
on C-4. Three different synthetic pathways were explored, compared and optimized to furnish the
imidazolines (Scheme 3). The biarylimidazole compounds were obtained directly from the corresponding
imidazolines.
N
N
N
H
N
H
COOMe
COOMe
O
OH
N
H
Anandamide
N
N
N
H
N
H
COOMe
COOMe
Scheme 2
Many approaches for the preparation of imidazoline have been described. Nevertheless, to propose an
efficient method for the synthesis of our target molecules, we considered that the use of methyl
2,3-diaminopropionate as starting material, leading to incorporate directly the carboxylate in C-4 position
of the heterocycle, constituted the most efficient way. The second point to develop our methodology
results in the difficulty to incorporate directly bicyclic moieties in C-2 position. The majority of the
procedures described proved to be inefficient for our target molecules. The precursors cannot be easily
employed in aromatic series (e.g. biphenylnitrile derivatives for example) or in a large set of compounds.

HETEROCYCLES, Vol. 68, No. 6, 2006
1151
However three methods focused our attention and employed precursors which can be easily obtained
from commercial bicyclic acids.
O
O
O
NH
g
f
b
R
N
c
R
NH2
4a-e
R
OH
R
OEt
O
5a-e
1a-e
R
OMe
h
Path 2
Path 3
a
Path 1
S
SMe
N
d
e
R
N
R
N
COOMe
R
N
H
6a-e
2a-e
3a-e
i
Compound
R
a
b
c
d
e
2-biphenyl
3-biphenyl
4-biphenyl
1-naphthyl
2-naphthyl
N
COOMe
R
N
H
7b-d
Reagents and conditions : a) methyl 2,3-diaminopropionate hydrochloride, AlMe3, toluene, 15 h, 50°C b) DIEA, HBTU,
HOBt, piperidine, CH2Cl2 , 24 h, 68 to 99% c) P4S10, toluene, reflux, 6 h, 45 to 99% d) CH3I, reflux, 4 h e) DIEA, methyl
2,3-diaminopropionate hydrochloride, MeOH, reflux, 28 h, 27 to 57% f) (Boc)2O, pyridine, NH4HCO3, dioxane, 24 h, 72 to
99% g) Et3OBF4, CH2Cl2, 24 h, 47 to 82% h) methyl 2,3-diaminopropionate hydrochloride, EtOH, reflux, 6 h, 24 to 60%
i) DBU, CCl4, CH3CN, pyridine, 24 h, 61 to 95%.
Scheme 3
Firstly, we tried to generate the imidazoline ring by reaction of a biaryl ester with methyl
2,3-diaminopropionate in the presence of trimethylaluminum (Scheme 3, Path 1).17,18 Aluminum organic
reagents play an increasingly important role in effecting simple chemical transformations. Several
examples reported preparation of 2-substituted imidazolines from ester. Nevertheless, the methodologies
ultimately proved to be inefficient for our target molecules and obliged us to consider another approach
(Scheme 3, Path 2). The procedure described by Gilbert and Rees was adapted.19,20 The methodology
involves condensation of diamines with different S-methylthioimidates. Thus, the different
biarylcarboxylic acids used as starting materials were converted in quantitative yields into corresponding
piperidine amides (1a-e) with HBTU as a coupling agent. The non-commercially 3-biphenylcarboxylic
acid was prepared using palladium-catalysed cross-coupling reaction between Grignard reagent and
3-bromobenzoic acid, according to a described procedure.21 The conversion of amides (1a-e) into
thioamides (2a-e) was achieved using phosphorus pentasulfide in refluxing toluene and the treatment

1152
HETEROCYCLES, Vol. 68, No. 6, 2006
with methyl iodide afforded the (S)-methylthioimidate salts (3a-e). No reaction was observed when amides
(1a-e) were refluxed in toluene or xylene with Lawesson’s reagent. The (S)-methylthioimidate salts (3a-
e) were not isolated but condensed in situ with the methyl 2,3-diaminopropionate in refluxing methanol
to provide the biarylimidazoline compounds (6b-e) in 27% to 57% yields (Table 1). However, this
synthetic pathway did not lead to ortho and meta substituted imidazolines (6a and 6b). The formation of
the (S)-methylthioimidate salts (3a) was highlighted by thin layer chromatography, but the condensation
with the diamino ester did not carry out. We have attributed this lack of reaction to the steric constraint
brought by the ortho-biphenyl moiety. Concerning compound (6b), the product could not be purified by
classical methodologies as flash-chromatography.
Compounds
Yield (Path 2)
Not obtained
Not purified
57 %
Yield (Path 3)
24 %
6a
6b
6c
6d
6e
56 %
60 %
27 %
34 %
48 %
59 %
Table 1. Yields for the cyclization into imidazolines (6a-e)
To continue with our investigation, we applied the procedure described by Jones and Ward22 (Scheme 3,
Path 3). The imidazoline ring was obtained by a condensation of an imino ether initially prepared with a
diamine. Thus, different biarylcarboxylic acids were first converted in high yields in primary amides
(4a-e) following Pozdnev’s method using (Boc)2O.23 The biarylcarboxylic acids were activated with
(Boc)2O into a corresponding mixed anhydrides as intermediates which readily react with ammonium
hydrogen carbonate. Treatment of these amides (4a-e) with triethyloxonium tetrafluoroborate gave the
corresponding imino ethers (5a-e).24 The different imidazolines (6a-e) were then obtained by
condensation of methyl 2,3-diaminopropionate with the imino ethers (5a-e). In order to optimize this
cyclization step, we investigated the effect of the solvent on the ring closure by LC-MS. The reaction
between the methyl 2,3-diaminopropionate and the imino ether (5c) was monitored by LC-MS and
carried out with five different solvents (chloroform, acetonitrile, ethanol, tetrahydrofurane and
dimethylformamide) in order to get the most wide range. Conversion rates according to solvent and time
were determined through molecular weights of the imino ether (5c) and the imidazoline product (6c)
(Chart 1). The highest conversion rate was obtained after 6 h in refluxing ethanol. Acetonitrile appeared
also to be a good solvent for cyclization, with a nearby conversion rate in the same time of reaction. All

HETEROCYCLES, Vol. 68, No. 6, 2006
1153
the conversion rates were limited by the formation of a by-product. The molecular weight of this by-
product supports the hypothesis of a partial recovery of the imino ether (5c) in primary amide (4c). This
recovery appeared to be more important in tetrahydrofurane and dimethylformamide, and was
accompanied in dimethylformamide by a light degradation of the imidazoline (6c). In chloroform,
cyclization seemed to be slower than in other solvents and stopped to evolve after 7 days.
70
60
50
chloroform
40
acetonitrile
ethanol
tetrahydrofurane
30
20
10
0
0
2
6
24
30
48
54
72
78
96
102
148
Time (h)
Chart 1
All imidazolines (6a-e) were then obtained and prepared according to this procedure with EtOH at reflux.
As regard to path 1, yields were improved and this methodology allowed to obtain all imidazolines
(6a-e). The preparation of imidazoles from imidazolines is well described.25-29 Different methods were
investigated and yields obtained were in the same range. The imidazolines (6b-d) were then
dehydrogenated into the corresponding imidazoles (7b-d) using 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in a mixture of carbone tetrachloride, pyridine and acetonitrile.
In conclusion, we described a versatile and efficient method to prepare different 2-aryl substituted
imidazolines and imidazoles. Optimization of the procedure was explored. The purification of the
products was found to be flexible enough to obtain appreciable quantities of compounds. This protocol
opens a way for the synthesis of other various 2-substituted imidazolines and imidazoles that can be
incorporated as a building unit with various biological and pharmacological properties.

1154
HETEROCYCLES, Vol. 68, No. 6, 2006
EXPERIMENTAL SECTION
General. THF was distilled from sodium/benzophenone prior to use. All other reagents and solvents
were obtained from commercial sources and used without further purification. Analytical TLC was
performed on precoated Kieselgel 60F254 plates (Merck) ; compounds were visualized by UV and/or with
iodine. Silica gel Kieselgel Si 60 (230-400 mesh, Merck) was used for chromatography. Mp were
determined with a Büchi 530 capillary melting point apparatus and remain uncorrected. The structures of
all compounds were supported by IR spectrum (FT-Bruker Vector 22 instrument) and, if possible, by 1H
NMR spectrum at 300 MHz on a Bruker DPX-300 spectrometer in DMSO-d6 or in CDCl3 at ambient
temperature. Chemical shifts (δ) are reported in ppm downfield from TMS, J values are in hertz.
Elemental analyses were performed by the “Service Central d’Analyses” at the CNRS, Vernaison, France.
LC-MS (APCI+) was performed on a Thermo Electron Surveyor MSQ system equipped with a TSK gel
Super-ODS (4.6 x 50 mm, 2 µm) and a DAD detector. Compounds were dissolved in MeOH and injected
through a 10 µL loop. Elution was performed with the following two systems: solution A (0.1 % formic
acid in H2O) and solution B (0.08 % formic acid, 20 % H2O, 79.92 % CH3CN). LC-MS retention times
were obtained, at flow rates of 2.75 mL/min, using a gradient run 100% eluent A during
1 min, from 100% eluent A to 50% eluent B over the next 5 min, then 50% eluent B during 1 min.
2-Biphenyl(piperidino)methanone (1a) To a mixture of 2-biphenylcarboxylic acid (1.00 g,
5.04 mmol), HBTU (3.83 g, 10.1 mmol) and HOBt (0.34 g, 2.52 mmol) in dry CH2Cl2 was added DIEA
(1.76 mL, 10.1 mmol) slowly dropwise. After stirring at rt for 45 min, piperidine (0.55 mL, 5.55 mmol)
was added slowly dropwise and the stirring was continued for 24 h. The reaction mixture was then
filtrated and the filtrate was concentrated in vacuo. The residue was purified by column chromatography
on silica gel (CH2Cl2/MeOH, 95:5) to provide 1a (1.33 g, 99%) as a white solid, mp 84-85°C.
IR : 1621 (CO), 841 (CH aromatic), 746 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 0.54 (m, 1H), 1.12 (m,
1H), 1.22 (m, 1H), 1.35 (m, 2H), 1.45 (m, 1H), 2.70 (m, 1H), 2.88 (m, 1H), 3.41 (m, 1H), 3.69
(m, 1H), 7.32-7.47 (m, 8H), 7.50 (d, 1H, J = 7.0 Hz). MS : m/z 266 (MH+).
3-Biphenyl(piperidino)methanone (1b) Starting from 3-biphenylcarboxylic acid (1.12 g, 5.65 mmol),
compound (1b) was synthesized using the procedure described for 1a. Purification by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5) gave 1.02 g (68%) as a white solid, mp 89-90°C.
IR : 1619 (CO), 741 (CH aromatic), 697 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.53 (m, 2H), 1.68 (m,
4H), 3.39 (m, 2H), 3.74 (m, 2H), 7.36 (m, 2H), 7.51 (m, 3H), 7.60 (d, 2H, J = 7.8 Hz), 7.62 (m, 2H).
MS : m/z 266 (MH+).

HETEROCYCLES, Vol. 68, No. 6, 2006
1155
4-Biphenyl(piperidino)methanone (1c) Starting from 4-biphenylcarboxylic acid (2.00 g, 10.1 mmol),
compound (1c) was obtained using the procedure described for 1a. Purification by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5) gave 2.52 g (94%) as a white solid, mp 98-99°C.
IR : 1631 (CO), 849 (CH aromatic), 744 (CH aromatic) cm-1. 1H NMR (DMSO-d6) : δ 1.51 (m, 3H), 1.61
(m, 3H), 3.33 (m, 2H), 3.52 (m, 2H), 7.40 (t, 1H, J = 7.2 Hz), 7.44-7.51 (m, 4H), 7.70 (d, 2H,
J = 8.1 Hz), 7.72 (d, 2H, J = 8.1 Hz). MS : m/z 266 (MH+).
1-Naphthyl(piperidino)methanone (1d) Similarly to the procedure described for 1a, compound (1d)
was prepared starting from 1-naphthoic acid (1.50 g, 8.71 mmol) and purified by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford 2.06 g (99%) as a white solid, mp 95-96°C.
IR : 1626 (CO), 815 (CH aromatic), 804 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.41 (m, 2H), 1.66 (m,
2H), 1.73 (m, 2H), 3.14 (m, 2H), 3.88 (m, 2H), 7.40-7.55 (m, 4H), 7.87-7.84 (m, 3H). MS : m/z 240
(MH+).
2-Naphthyl(piperidino)methanone (1e) As described for 1a, compound (1e) was obtained from
2-naphthoic acid (2.00 g, 11.6 mmol) and purified by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) to give 2.75 g (99%) as a white solid, mp 110-111°C. IR : 1615 (CO), 834
(CH aromatic), 808 (CH aromatic), 760 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.26 (m, 2H), 1.69
(m, 4H), 3.39 (m, 2H), 3.78 (m, 2H), 7.50 (m, 3H), 7.85 (m, 3H), 7.89 (s, 1H). MS : m/z 240 (MH+).
2-Biphenyl(piperidino)methanethione (2a) To a suspension of 1a (1.20 g, 4.52 mmol) in dry toluene
(100 mL) was added phosphorus pentasulfide (0.70 g, 3.17 mmol). The reaction mixture was refluxed
under nitrogen atmosphere for 6 h, filtered and evaporated in vacuo. The crude residue was purified by
column chromatography on silica gel (CH2Cl2) to provide 2a (1.06 g, 83%) as a yellow solid,
mp 128-129°C. IR : 1492 (CS), 760 (CH aromatic), 743 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 0.74
(m, 1H), 1.26 (m, 1H), 1.44 (m, 3H), 1.64 (m, 1H), 2.92 (m, 1H), 3.20 (m, 1H), 4.00 (m, 1H), 4.21
(m, 1H), 7.33-7.48 (m, 8H), 7.64 (d, 1H, J = 6.9 Hz). MS : m/z 282 (MH+).
3-Biphenyl(piperidino)methanethione (2b) Starting from 1b (1.50 g, 5.65 mmol), compound (2b) was
synthesized using the procedure described for 2a. Purification by column chromatography on silica gel
(CH2Cl2) gave 0.72 g (45%) as a yellow solid, mp 75-76°C. IR : 1488 (CS), 757 (CH aromatic), 701
(CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.60 (m, 2H), 1.78 (m, 2H), 2.30 (m, 2H), 3.58 (m, 2H), 4.40
(m, 2H), 7.25 (m, 1H), 7.39 (m, 2H), 7.44 (d, 2H, J = 7,3 Hz), 7.48 (t, 1H, J = 8.3 Hz), 7.56 (d, 1H,
J = 8.3 Hz), 7.58 (s, 1H), 7.61 (d, 1H, J = 8.3 Hz). MS : m/z 282 (MH+).

1156
HETEROCYCLES, Vol. 68, No. 6, 2006
4-Biphenyl(piperidino)methanethione (2c) Starting from 1c (2.45 g, 9.23 mmol), compound (2c) was
obtained using the procedure described for 2a. Purification by column chromatography on silica gel
(CH2Cl2) gave 1.30 g (50%) as a yellow solid, mp 182-183°C. IR : 1496 (CS), 768 (CH aromatic),
694 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.61 (m, 2H), 1.80 (m, 4H), 3.60 (m, 2H), 4.38 (m, 2H),
7.37 (m, 3H), 7.45 (t, 2H, J = 7.1 Hz), 7.56 (d, 2H, J = 7.9 Hz), 7.59 (d, 2H, J = 7.9 Hz). MS : m/z 282
(MH+).
1-Naphthyl(piperidino)methanethione (2d) Similarly to the procedure described for 2a, compound
(2d) was prepared starting from 1d (1.50 g, 6.27 mmol) and purified by column chromatography on
silica gel (CH2Cl2) to afford 1.58 g (99%) as a yellow solid, mp 116-117°C. IR : 1491 (CS), 796
(CH aromatic), 773 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.46 (m, 2H), 1.74 (m, 2H), 1.91 (m, 2H),
3.20 (m, 2H), 4.48 (m, 1H), 4.57 (m, 1H), 7.52-7.34 (m, 4H), 7.78-7.87 (m, 3H). MS : m/z 256 (MH+).
2-Naphthyl(piperidino)methanethione (2e) As described for 2a, compound (2e) was obtained from 1e
(2.72 g, 11.4 mmol) and purified by column chromatography on silica gel (CH2Cl2) to give 1.74 g (60%)
as a yellow solid, mp 135-136°C. IR : 1493 (CS), 858 (CH aromatic), 821 (CH aromatic), 746
(CH aromatic) cm-1. 1H NMR (DMSO-d6) : δ 1.53 (m, 2H), 1.72 (m, 4H), 3.52 (m, 2H), 4.34 (m, 2H),
7.40 (d, 1H, J = 8.8 Hz), 7.55 (t, 2H, J = 8.8 Hz), 7.80 (m, 1H), 7.92 (d, 2H, J = 7.9 Hz), 7.94 (s, 1H).
MS : m/z 256 (MH+).
2-Phenylbenzamide (4a) To a mixture of 2-biphenylcarboxylic acid (1.50 g, 7.57 mmol) and di-tert-
butyl dicarbonate (2.15 g, 9.84 mmol) in dioxane (50 mL) was added pyridine (0.60 mL, 7.57 mmol).
After stirring at rt for 15 min, ammonium hydrogen carbonate (0.78 g, 9.84 mmol) was added and the
stirring was purchased for 24 h. The reaction mixture was then diluted with water and the resulting
precipitate was collected, washed with water, dried and purified by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) to provide 4a (1.08 g, 72%) as a white solid, mp 179-180°C. IR : 1642 (CO),
1618 (NH), 1397 (CN), 776 (CH aromatic), 741 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 5.27 (bs, 1H),
5.64 (bs, 1H), 7.39 (t, 1H, J = 7.5 Hz), 7.46 (m, 6H), 7.50 (dd, 1H, J = 7.5 Hz, J = 1.4 Hz), 7.79 (dd, 1H,
J = 7.5 Hz, J = 1.4 Hz). MS : m/z 198 (MH+).
3-Phenylbenzamide (4b) Starting from 3-biphenylcarboxylic acid (1.50 g, 7.57 mmol), compound (4b)
was synthesized using the procedure described for 4a. Purification by column chromatography on silica
gel (CH2Cl2/MeOH, 95:5) gave 1.40 g (94%) as a white solid, mp 172-173°C. IR : 1668 (CO),
1628 (NH), 1394 (CN), 741 (CH aromatic), 699 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 5.87 (bs, 1H),

HETEROCYCLES, Vol. 68, No. 6, 2006
1157
6.19 (bs, 1H), 7.40 (t, 1H, J = 7.3 Hz), 7.48 (t, 2 H, J = 7.3 Hz), 7.54 (t, 1H, J = 7.6 Hz), 7.63 (d, 2H,
J = 7.3 Hz), 7.77 (d, 1H, J = 7.6 Hz), 7.80 (d, 1H, J = 7.6 Hz), 8.08 (s, 1H). MS : m/z 198 (MH+).
4-Phenylbenzamide (4c) Starting from 4-biphenylcarboxylic acid (2.50 g, 12.6 mmol), compound (4c)
was obtained using the procedure described for 4a. Purification by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) gave 2.41 g (97%) as a white solid, mp 234-235°C. IR : 1647 (CO), 1616 (NH),
1410 (CN), 852 (CH aromatic), 738 (CH aromatic) cm-1. 1H NMR (DMSO-d6) : δ 7.41 (m, 2H), 7.50
(t, 1H, J = 7.1 Hz), 7.73 (d, 2H, J = 7.5 Hz), 7.76 (d, 2H, J = 8.3 Hz), 7.98 (d, 2H, J = 8.3 Hz), 8.05
(bs, 2H). MS : m/z 198 (MH+).
1-Naphthamide (4d) Similarly to the procedure described for 4a, compound (4d) was prepared starting
from 1-naphthoic acid (2.00 g, 11.6 mmol) and purified by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) to afford 1.95 g (98%) as a white solid, mp 206-207°C. IR : 1662 (CO), 1616
(NH), 1366 (CN), 779 (CH aromatic), 734 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 6.02 (bs, 2H), 7.49
(t, 1H, J = 8.2 Hz), 7.58 (m, 2H), 7.73 (d, 1H, J = 7.0 Hz), 7.90 (d, 1H, J = 8.2 Hz), 7.96 (d, 1H,
J = 8.2 Hz), 8.44 (d, 1H, J = 8.2 Hz). MS : m/z 172 (MH+).
2-Naphthamide (4e) As described for 4a, compound (4e) was obtained from 2-naphthoic acid (2.00 g,
11.6 mmol) and purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to give 1.97 g
(99%) as a white solid, mp 197-198°C. IR : 1655 (CO), 1611 (NH), 1414 (CN), 840 (CH aromatic),
788 (CH aromatic), 721 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 5.82 (bs, 1H), 6.24 (bs, 1H), 7.59
(m, 2H), 7.87 (d, 1H, J = 8.6 Hz), 7.90 (d, 1H, J = 9.7 Hz), 7.94 (d, 1H, J = 7.6 Hz), 7.96 (d, 1H,
J = 8.6 Hz), 8.37 (s, 1H). MS : m/z 172 (MH+).
Ethyl-2-phenyl-1-benzenecarboximidate (5a) To a solution of 4a (0.93 g, 4.72 mmol) in CH2Cl2
(100 mL) cooled at 0°C was added triethyloxonium hexafluorophosphate (1.43 g, 5.19 mmol). After
stirring at rt for 24 h, the reaction mixture was poured into ice-cold solution of sodium carbonate 1M
(150 mL). The layers were separated by decantation : the organic layer was recuperated and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) to provide 5a (0.87 g, 82%) as a yellow oil. IR : 1638 (CN), 1074 (CO),
1
774 (CH aromatic), 745 (CH aromatic) cm-1. H NMR (CDCl3) : 1.06 (t, 3H, J = 7.1 Hz), 4.08 (q, 2H,
J = 7.1 Hz), 7.33-7.43 (m, 7H), 7.48 (t, 1H, J = 7.6 Hz), 7.57 (d, 1H, J = 7.6 Hz). MS : m/z 226 (MH+).

1158
HETEROCYCLES, Vol. 68, No. 6, 2006
Ethyl-3-phenyl-1-benzenecarboximidate (5b) Starting from 4b (1.22 g, 6.19 mmol), compound (5b)
was synthesized using the procedure described for 5a. Purification by column chromatography on silica
gel (CH2Cl2/MeOH, 95:5) gave 0.66 g (47%) as a yellow oil. IR : 1636 (CN), 1074 (CO), 762
(CH aromatic), 717 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.45 (t, 3H, J = 7.1 Hz), 4.39 (q, 2H,
J = 7.1 Hz), 7.40 (t, 1H, J = 7.1 Hz), 7.48 (t, 1H, J = 7.9 Hz), 7.50 (t, 2H, J = 7.1 Hz), 7.62 (d, 2H,
J = 7.1 Hz), 7.70 (d, 1H, J = 7.9 Hz), 7.75 (d, 1H, J = 7.9 Hz), 7.98 (s, 1H). MS : m/z 226 (MH+).
Ethyl-4-phenyl-1-benzenecarboximidate (5c) Starting from 4c (2.39 g, 12.1 mmol), compound (5c)
was obtained using the procedure described for 5a. Purification by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) gave 1.64 g (60%) as a yellow oil. IR : 1627 (CN), 1085 (CO), 774
(CH aromatic), 737 (CH aromatic) cm-1. 1H NMR (DMSO-d6) : δ 1.34 (t, 3H, J = 7.1 Hz), 4.27 (q, 2H,
J = 7.1 Hz), 7.41 (t, 1H, J = 7.1 Hz), 7.48 (dd, 2H, J = 7.6 Hz, J = 7.1 Hz), 7.73 (d, 2H, J = 8.6 Hz), 7.76
(d, 2H, J = 8.6 Hz), 7.62 (d, 2H, J = 7.6 Hz). MS : m/z 226 (MH+).
Ethyl-1-naphthalenecarboximidate (5d) Similarly to the procedure described for 5a, compound (5d)
was prepared starting from 4d (1.69 g, 9.87 mmol) and purified by column chromatography on silica gel
(CH2Cl2/MeOH, 95:5) to afford 1.08 g (55%) as a yellow oil. IR : 1639 (CN), 1086 (CO),
801 (CH aromatic), 777 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.48 (t, 3H, J = 7.0 Hz), 4.51 (q, 2H,
J = 7.0 Hz), 7.48 (t, 1H, J = 7.0 Hz), 7.54 (m, 2H), 7.60 (t, 1H, J = 7.0 Hz), 7.88 (m, 2H), 8.12 (d, 1H,
J = 7.6 Hz). MS : m/z 200 (MH+).
Ethyl-2-naphthalenecarboximidate (5e) As described for 5a, compound (5e) was obtained from 4e
(2.36 g, 13.8 mmol) and purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to give
1.70 g (62%) as a yellow oil. IR : 1638 (CN), 1077 (CO), 861 (CH aromatic), 819 (CH aromatic),
754 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 1.51 (t, 3H, J = 7.1 Hz), 4.46 (q, 2H, J = 7.1 Hz),
7.52-7.60 (m, 2H), 7.80-7.98 (m, 4H), 8.32 (d, 1H, J = 8.2 Hz). MS : m/z 200 (MH+).
Methyl 2-(2-biphenyl)-4,5-dihydro-1H-5-imidazolecarboxylate (6a)
Method A: compound (6a) could not be obtained from method A.
Method B : To a suspension of 5a (0.50 g, 2.2 mmol) in dry EtOH (50 mL) was added methyl
2,3-diaminopropionate hydrochloride (0.41 g, 2.66 mmol). The reaction mixture was softly refluxed
under nitrogen atmosphere for 7 days. The solvent was then removed in vacuo and the crude residue was
purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford 6b (0.15 g, 24%) as a

HETEROCYCLES, Vol. 68, No. 6, 2006
1159
yellow oil. IR : 1737 (CO), 1614 (CN), 779 (CH aromatic), 743 (CH aromatic) cm-1. 1H NMR (CDCl3) :
δ 3.74 (s, 3H), 3.78-3.82 (m, 2H), 4.43 (t, 1H, J = 9.4 Hz), 7.34-7.42 (m, 7H), 7.49 (t, 1H, J = 7.6 Hz),
7.78 (d, 1H, J = 7.6 Hz). MS : m/z 281 (MH+). Anal. Calcd. for C17H16N2O2 : C, 72.84; H, 5.75; N, 9.99.
Found : C, 73.02; H, 5.48; N, 9.96.
Methyl 2-(3-biphenyl)-4,5-dihydro-1H-5-imidazolecarboxylate (6b)
Method A: compound (6b) could not be isolated from method A.
Method B : As described for 6a, compound (6b) was obtained from 5b (0.50 g, 2.2 mmol) and purified
by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to give 0.35 g (56%) as a yellow oil. IR :
1771 (CO), 1623 (CN), 763 (CH aromatic), 717 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 3.70 (s, 3H),
3.84 (m, 1H), 3.94 (m, 1H), 4.63 (dd, 1H, J = 7.5 Hz, J = 11.0 Hz), 7.40 (t, 1H, J = 7.5 Hz), 7.50 (t, 2H,
J = 7.5 Hz), 7.54 (t, 1H, J = 8.0 Hz), 7.13 (d, 2H, J = 7.5 Hz), 7.80 (d, 1H, J = 8.0 Hz), 7.87 (d, 1H,
J = 8.0 Hz), 8.14 (s, 1H). MS : m/z 281 (MH+). Anal. Calcd. for C17H16N2O2 : C, 72.84; H, 5.75; N, 9.99.
Found : C, 72.65; H, 5.41; N, 10.08.
Methyl 2-(4-biphenyl)-4,5-dihydro-1H-5-imidazolecarboxylate (6c)
Method A : The thioamide (2c) (0.50 g, 1.78 mmol) was heated under reflux in methyl iodide (10 mL)
under nitrogen atmosphere for 4 h. The solvent was removed in vacuo and the residue azeotroped with
methanol (2 × 5 mL). The residue was dissolved in dry methanol (10 mL) and a solution of methyl
2,3-diaminopropionate hydrochloride (0.40 g, 1.78 mmol) and DIEA (0.93 mL, 5.33 mmol) in minimum
of dry methanol was added. The reaction mixture was refluxed under nitrogen atmosphere for 2 h, left at
rt for 24 h and then refluxed for 2 h. The solvent was evaporated in vacuo and the resulting residue was
purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to provide 6c
(0.29 g, 57%) as a pale orange solid, mp 149-150°C. IR : 1750 (CO), 1618 (CN), 774 (CH aromatic),
737 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 3.79 (s, 3H), 4.14 (d, 2H, J = 7.4 Hz), 4.59 (t, 1H,
J = 7.4 Hz), 7.39 (t, 1H, J = 7.4 Hz), 7.45 (d, 2H, J = 7.4 Hz), 7.60 (d, 2H, J = 7.4 Hz), 7.63 (d, 2H,
J = 8.1 Hz), 7.87 (d, 2H, J = 8.1 Hz). MS : m/z 281 (MH+). Anal. Calcd. for C17H16N2O2 : C, 72.84;
H, 5.75; N, 9.99. Found : C, 72.73; H, 5.94; N, 9.87.
Method B : Starting from 5c (1.40 g, 6.22 mmol), compound (6c) was obtained using the method B
described for 6a. Purification by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) gave 1.05 g
(60%) as a pale orange solid.

1160
HETEROCYCLES, Vol. 68, No. 6, 2006
Methyl 2-(1-naphthyl)-4,5-dihydro-1H-5-imidazolecarboxylate (6d)
Method A : As described for 6b, compound (6d) was obtained from 2d (1.50 g, 5.87 mmol) and purified
by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to give 0.40 g (27%) as an orange oil.
IR : 1755 (CO), 1618 (CN), 801 (CH aromatic), 777 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 3.82
(s, 3H), 4.20 (d, 2H, J = 8.7 Hz), 4.63 (t, 1H, J = 8.7 Hz), 7.47 (t, 1H, J = 7.2 Hz), 7.54 (m, 2H), 7.74
(d, 1H, J = 7.2 Hz), 7.87 (dd, 1H, J = 7.2 Hz, J = 2.0 Hz), 7.92 (d, 1H, J = 8.6 Hz), 8.62 (d, 1H,
J = 8.1 Hz). MS : m/z 255 (MH+). Anal. Calcd. for C15H14N2O2 : C, 70.85; H, 5.55; N, 11.02. Found :
C, 70.74; H, 5.78; N, 10.93.
Method B : Starting from 5d (1.62 g, 8.13 mmol), compound (6d) was synthesized using the method B
described for 6a. Purification by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) gave 0.70 g
(34%) as an orange oil.
Methyl 2-(2-naphthyl)-4,5-dihydro-1H-5-imidazolecarboxylate (6e)
Method A : Similarly to the method A described for 6b, compound (6e) was prepared starting from 2e
(0.50 g, 1.96 mmol) and purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to
afford 0.24 g (48%) as a white solid, mp 195-196°C. IR : 1747 (CO), 1611 (CN), 869 (CH aromatic),
825 (CH aromatic), 751 (CH aromatic) cm-1. 1H NMR (DMSO-d6) : δ 3.28 (s, 3H), 3.75 (m, 2H), 4.74
(t, 1H, J = 7.4 Hz), 7.23 (m, 2H), 7.44 (d, 1H, J = 8.7 Hz), 7.58 (d, 2H, J = 8.7 Hz), 7.69 (d, 1H,
J = 8.1 Hz), 8.17 (s, 1H), 10.62 (bs, 1H). MS : m/z 255 (MH+). Anal. Calcd. for C15H14N2O2 : C, 70.85;
H, 5.55; N, 11.02. Found : C, 70.68; H, 5.84, N, 10.87.
Method B : Compound (6e) was prepared from compound (5e) (1.23 g, 6.18 mmol) using the method B
described for 6a and purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) to provide
0.93 g (59%) as a white solid.
Methyl 2-(3-biphenyl)-1H-5-imidazolecarboxylate (7b) To a solution of 6b (0.17 g, 0.61 mmol) in
carbon tetrachloride (10 mL), pyridine (10 mL) and acetonitrile (15 mL) was added DBU (0.37 mL,
2.43 mmol) slowly dropwise. The reaction mixture was stirred at room temperature for 24 h and then
evaporated in vacuo. The crude residue was dissolved in CH2Cl2 and the organic layer was washed with a
solution of HCl (0.5 N ), dried over MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (CH2Cl2/MeOH, 4:1) to give 7b (0.10 g, 61%) as a white solid, mp
186-187°C. IR : 1688 (CO), 758 (CH aromatic), 725 (CH aromatic) cm-1. 1H NMR (CDCl3) : δ 3.88
(s, 3H), 7.38 (t, 1H, J = 7.0 Hz), 7.43 (t, 2H, J = 7.0 Hz), 7.48 (t, 1H, J = 7.9 Hz), 7.56 (d, 2H,

HETEROCYCLES, Vol. 68, No. 6, 2006
1161
J = 7.0 Hz), 7.60 (t, 1H, J = 7.9 Hz), 7.83 (s, 1H), 7.87 (d, 1H, J = 7.9 Hz), 8.13 (s, 1H). MS : m/z 279
(MH+). Anal. Calcd. for C17H14N2O2 : C, 73.37; H, 5.07; N, 10.07. Found : C, 73.58; H, 5.39; N, 10.15.
Methyl 2-(4-biphenyl)-1H-5-imidazolecarboxylate (7c) Starting from 6c (0.18 g, 0.64 mmol),
compound (7c) was obtained using the procedure described for 7b. Purification by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5) gave 0.17 g (95%) as a white solid, mp 243-244°C.
IR : 1724 (CO), 775 (CH aromatic), 736 (CH aromatic) cm-1. 1H NMR (DMSO-d6) : δ 3.80 (s, 3H), 7.39
(t, 1H, J = 7.2 Hz), 7.51 (t, 2H, J = 7.2 Hz), 7.75 (d, 2H, J = 7.2 Hz), 7.81 (d, 2H, J = 8.1 Hz), 8.07
(d, 2H, J = 8.1 Hz), 8.23 (s, 1H). MS : m/z 279 (MH+). Anal. Calcd. for C17H14N2O2 : C, 73.37; H, 5.07;
N, 10.07. Found : C, 73.32; H, 4.97; N, 9.86.
Methyl 2-(1-naphthyl)-1H-5-imidazolecarboxylate (7d) Similarly to the procedure described for 7b,
the compound was prepared starting from 6d (0.40 g, 1.57 mmol) and purified by column
chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford 0.37 g (93%) as a white solid,
mp 226-227°C. IR : 1720 (CO), 808 (CH aromatic), 774 (CH aromatic) cm-1. 1H NMR (DMSO-d6) :
δ 3.82 (s, 3H), 7.52 (t, 1H, J = 7.3 Hz), 7.60-7.64 (m, 3H), 7.84 (d, 1H, J = 6.7 Hz), 7.96-8.09 (m, 3H).
MS : m/z 253 (MH+). Anal. Calcd. for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10. Found : C, 71.40;
H, 4.91; N, 11.03.
REFERENCES
1
2
3
C. Adessi and C. Soto, Curr. Med. Chem., 2002, 9, 963.
A. S. Ripka and D. H. Rich, Curr. Opin. Chem. Biol., 1998, 2, 441.
S. Hanessian, G. McNaughton-Smith, H. G. Lombart, and W. D. Lubell, Tetrahedron, 1997, 53,
12789.
4
5
K. S. Kee and S. D. Jois, Curr. Pharm. Design, 2003, 9, 1209.
P. Angibaud, A. K. Saha, X. Bourdrez, D. W. End, E. Freyne, P. Lezouret, G. Mannens,
L. Mevellec, C. Meyer, I. Pilatte, V. Poncelet, B. Roux, G. Smets, J. Van Dun, M. Venet, and
W. Wouters, Bioorg. Med. Chem. Lett., 2003, 13, 4361.
6
7
8
R. Millet, J. Domarkas, R. Houssin, P. Gilleron, J.-F. Goossens, P. Chavatte, C. Loge,
N. Pommery, J. Pommery, and J.-P. Hénichart, J. Med. Chem., 2004, 47, 6812.
P. B. Timmermans, D. J. Carini, A. T. Chiu, J. V. Duncia, W. A. Proce, G. J. Wells, P. C. Wong,
R. R. Wexler, and A. L. Johnson, Hypertension, 1991, 18, 5, III 136.
C. A. Bernhart, P. M. Perreaut, B. P. Ferrari, Y. A. Muneaux, J.-L. A. Assens, J. Clément,
F. Haudricourt, C. F. Muneaux, J. E. Taillades, M-A. Vignal, J. Gougat, P. R. Guiraudou,

1162
HETEROCYCLES, Vol. 68, No. 6, 2006
C. A. Lacour, A. Roccon, C. F. Cazaubon, J.-C. Brelière, G. Le Fur, and D. Nisato, J. Med. Chem.,
1993, 36, 3371.
9
B. Le Bourdonnec, E. Meulon, S. Yous, J.-F. Goossens, R. Houssin, and J.-P. Hénichart,
J. Med. Chem., 2000, 43, 2685.
10
B. Le Bourdonnec, C. Cauvin, E. Meulon, S. Yous, J.-F. Goossens, F. Durant, R. Houssin, and
J.-P. Hénichart, J. Med. Chem., 2002, 45, 4794.
11
12
13
14
M. Mimeault, N. Pommery, N. Wattez, C. Bailly, and J.-P. Hénichart, Prostate, 2003, 56, 1.
M. Bifulco and V. Di Marzo, Nat. Med., 2002, 8, 547.
V. Di Marzo, D. Melck, L. De Petrocellis, and T. Bisogno, Prostag. Oth. Lipid M., 2000, 61, 43.
L. De Petrocellis, D. Melck, A. Palmisano, T. Risogno, C. Laezza, M. Bifulco, and V. Di Marzo,
Proc. Natl. Acad. Sci. USA, 1998, 95, 8375.
15
16
M. Mor, S. Rivara, A. Lodola, P. V. Plazzi, G. Tarzia, A. Duranti, A. Tontini, G. Piersanti,
S. Kathuria, and D. Piomelli, J. Med. Chem., 2004, 47, 4998.
G. G. Muccioli, N. Fazio, G. K. E., Scriba, W. Poppitz, F. Cannata, J. H., Poupaert, J. Wouters,
and D. M. Lambert, J. Med. Chem., 2006, 49, 417.
17
18
19
20
21
22
23
24
25
26
27
28
29
C. H. Oh, C. S. Lee, J. S. Lee, and J. H. Cho, Arch. Pharm. Pharm. Med. Chem., 2003, 336, 504.
G. Neef, U. Eder, and G. Sauer, J. Org. Chem., 1981, 46, 2824.
I. H. Gilbert and D. C. Rees, Tetrahedron, 1995, 51, 22, 6315.
R. C. F. Jones and G. J. Ward, Tetrahedron Lett., 1988, 29, 3853.
N. A. Bumagin and E. V. Luzikova, J. Organomet. Chem., 1997, 532, 271.
R. C. F. Jones and G. J. Ward, Tetrahedron Lett., 1988, 29, 3853.
V. F. Pozdnev, Tetrahedron Lett., 1995, 36, 39, 7115.
R. J. Bergeron, J. S. McManis, J. B. Dionis, and J. R. Garlich, J. Org. Chem., 1985, 50, 2780.
P. P. Fu and R. G. Harvey, Chem. Rev., 1978, 78, 317.
J. Cossy and D. Belotti, Org. Lett., 2002, 4, 2557.
D. Walker and J. D. Hiebert, Chem. Rev., 1967, 67, 153.
R. D. Singer and P. J. Scammells, Tetrahedron Lett., 2001, 42, 6831.
U. Tistam, M. Harre, T. Heckrodt, and H. Weinmann, Tetrahedron Lett., 2001, 42, 5385.