An efficient method for the preparation of new analogs of leucettamine B under solvent-free microwave irradiation

Article abstract of DOI:10.3987/COM-08-11594

A simple and efficient microwave-assisted protocol has been developed for the synthesis of new 2-amino-3,4-dihydro-4H-imidazol-4-one derivatives of leucettamine B. This solvent-free protocol involves sulphur/nitrogen displacement of 2-ethylthio-5-aryliden

Full text of DOI:10.3987/COM-08-11594

HETEROCYCLES, Vol. 78, No. 5, 2009
1191
HETEROCYCLES, Vol. 78, No. 5, 2009, pp. 1191 - 1203. © The Japan Institute of Heterocyclic Chemistry
Received, 11th November, 2008, Accepted, 29th December, 2008, Published online, 9th January, 2009
DOI: 10.3987/COM-08-11594
AN EFFICIENT METHOD FOR THE PREPARATION OF NEW
ANALOGS OF LEUCETTAMINE B UNDER SOLVENT-FREE
MICROWAVE IRRADIATION
Mansour Debdab,a Steven Renault,a Samar Eid,a Olivier Lozach,b Laurent
Meijer,b François Carreaux,*a and Jean Pierre Bazureau*a
a
Université de Rennes 1, Sciences Chimiques de Rennes, UMR CNRS 6226,
Groupe Ingénierie Chimique & Molécules pour le Vivant (ICMV), Bât. 10A,
Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 RENNES
Cedex, France. b Station Biologique de Roscoff, CNRS, Protein Phosphorylation
and Human Disease, Place Georges Teissier, BP 74, 29682 ROSCOFF, France
E-mail: francois.carreaux@univ-rennes1.fr
Abstract – A simple and efficient microwave-assisted protocol has been
developed for the synthesis of new 2-amino-3,4-dihydro-4H-imidazol-4-one
derivatives of leucettamine B. This solvent-free protocol involves sulphur/nitrogen
displacement of 2-ethylthio-5-arylidene-imidazolone 5 with a variety of
functionalized polar primary amines 6 and this general method afforded a small
library of the desired pure products 7a-n in yields ranging from 33 to 92% in
moderate reaction times (30-100 minutes).
INTRODUCTION
The 2-aminoimidazolone ring is a widely used structural motif in drug discovery. In particular, the
2-aminoimidazolone ring of type 1 (Figure 1) constitutes an interesting pharmacophore that displays a
wide variety of pharmacological activities.1 During these last few years, an increasingly important number
of natural products comprising the 2-aminoimidazolone moiety have been isolated from marine sponges.2
Hymenialdisine is one of the most known alkaloids taking into account its biological activity as potent
inhibitor of cyclin-dependent kinases, glycogen synthase kinase-3β and casein kinase 1.3 Among this class
of compounds, the leucettamine B, isolated from the sponge Leucetta microraphis Haeckel (alcarea class)
of the Argulpelu Reef in Palau,4 has received little attention although the synthesis of this natural product
was reported.5

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HETEROCYCLES, Vol. 78, No. 5, 2009
R1HN
R2
N
N
R3
O
1
O
Br
O
NH
H2N
Me
N
H2N
H
O
NH
N
N
N
O
O
Leucettamine B
Hymenialdisine
Figure 1. Structure of some marine alkaloids containing a ring of type 1
In the context of our program to prepare libraries of small heterocyclic rings with a potential therapeutic
interest,6 we focused our attention on the 2-aminoimidazolone nucleus of leucettamine B. The few
syntheses of analogs, reported in the literature, used the Knoevenagel reaction for the stereoselective
exocyclic double bond formation, but suffer some limitations concerning the degree of molecular diversity
of the final step. Two methods of activation of C=S bond have been used for the condensation of amines on
the arylidene thiohydantoin. The TBHP promoted transamination reaction gives good yields with long
reaction time (> 24h) but does not seem adapted for combinatorial and/or parallel synthesis due to the use
of a large excess of amines (>16 equiv.) which complicates the purification of the final products
(chromatography).5b Activation via thioether constitutes also a route to 2-aminoimidazolones of type 1,
however displacement with amines in a conventional thermal process requires harsh reaction conditions
and gives good results only with non-sterically hindered primary amines.7,8
In the light of these observations and due to the potential biological interest of this class of compounds, we
wished to develop an efficient methodology for the generation of a collection of compounds containing a
ring of type 1 and, more particularly of analogs of leucettamine B with a high degree of molecular diversity.
Recently, we have described a practical protocol for the preparation of a parallel solution-phase library of
2-alkylthio-5-arylidene imidazolone by one-pot three-component domino reaction.6b This flexible strategy
could be useful for the synthesis of analogs of leucettamine B, if we are able to develop an efficient method
for the sulfur/nitrogen displacement with a large wide range of amines. The utility of microwave
irradiation9 (µw) to carry out an organic reaction has now become a regular feature. A key advantage of
modern scientific microwave apparatus is the ability to control reaction conditions very specifically,
monitoring temperature-pressure and the reaction times. The use of this technology for the rapid synthesis
of molecules is a useful tool for the medicinal chemistry community, for whom reaction speed is of great
importance.10
To the best of our knowledge, the benefits of performing the substitution reaction of 2-alkylthio
imidazolone with amines under solvent-free microwave irradiation has not been demonstrated to date. So,

HETEROCYCLES, Vol. 78, No. 5, 2009
1193
we report in this paper our results concerning this new methodology to generate a small library of
leucettamine B analogs.
RESULTS AND DISCUSSION
2-Ethylthio 3,5-dihydro-4H-imidazol-4-one 5 was prepared in 62% yield by one-pot three-component
domino reaction (Scheme 1), using the following partners: aromatic aldimine 3, iodoethane 4 and
2-thioxo-imidazolidin-4-one 2 which is easily available by reaction between methyl glycinate and
commercial methyl isothiocyanate.6b With compound 5 in hand, we envisioned the scope and generality of
the microwave-assisted sulphur/nitrogen displacement with various selected amines according to the
previous biological activities observed on this scaffold.11
For microwave irradiation, domestic microwave ovens are frequently used in organic synthesis, due to
their low cost and immediate availability. However, mono-mode microwave reactors, specifically
designed for chemical synthesis, provide homogeneous heating, temperature control and importantly,
improved safety features.12 The microwave instrument (Synthewave® 402 reactor) comprises a
mono-mode cavity that operates at a frequency of 2.45 GHz with a continuous microwave irradiation
power from 0 to 300 watts. Inside the cavity, the quartz reactor was exposed to microwave irradiation, and
the reaction temperature is measured with the aid of an IR captor13 (infrared thermometry). The software
algorithm regulates the microwave out-put power so that the preselected maximum temperature is
maintained for the desired reaction/irradiation time.
1
O
O
2
7
O
O
6
3
H
N1
4
S
RNH
2
5
EtS
Me
N
(i)
N
O
O
(ii)
N
+
+
Et-I
5
3 N
Me
N
N
6, R-NH2
Me
4 O
O
O
3
4
2
7
5
Scheme 1. Reagents and reaction conditions: (i) 2 1 equiv., 3 1 equiv., 4 1.5 equiv., K2CO3 0.5
®
equiv., MeCN, 60°C, 14 h, 62%. (ii) 6 1-5 equiv., µω (Synthewave 402 reactor), 100-155°C,
20-100 min.
For optimization of reaction conditions under microwave dielectric heating, the polar primary amines
employed were successively aniline 6a and different substituted aliphatic amines such as
N-(3-aminopropyl)imidazole 6h and 3-aminopropanol 6m. The other parameters of this reaction were
respectively the reaction temperature (from 100 to 155°C), the power for microwave irradiation (from 150
to 300 Watt), the reaction concentration (ratio 5/6 from 1 to 4) and the reaction time (from 15 to 60 min.).
In order to simplify and generalize the process, the reaction mixtures are precipitated in ethanol (or
chloroform) and filtered off to eliminate starting materials and impurities.

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HETEROCYCLES, Vol. 78, No. 5, 2009
The values for optimization of reaction conditions were presented in Table 1. At high temperature,
compound 7a was obtained in moderate yield (58%) using 4 equivalents of 6a with a microwave power of
240 watts during 40 minutes (entry 3). When the sulphur/nitrogen displacement was realized in a
preheated oil bath at 155°C using exactly the same conditions (40 min., 4 equiv. of 6a) and in the same
open reactor, a yield of 10% of isolated pure product 7a was obtained. Comparing the conventional and
the solvent-free heating, it seems reasonable to propose that the significantly higher yield may be
explained by the rapid heating under microwave irradiation (microwave-flash heating). The desired
reaction temperature of 155°C is rapidly reached within 3 minutes by direct microwave heating (in core),
in contrast to conventional thermal heating utilizing an oil bath, preheated to 155°C. Taking advantage of
the broad range of temperature offered by controlled quartz vessel microwave heating, we found that the
irradiation of 2-ethylthio imidazolone 5 (mp = 150-152°C), with 2 equivalents of liquid
N-(3-aminopropyl)imidazole 6h at 120°C (240 W) for 60 minutes, allowed full conversion to the product
7h which was isolated in 72% yield after crystallization in chloroform (entry 6). With 3-aminopropanol
6m, the product 7m was conveniently prepared in good yield (81%) by shortening the microwave
irradiation time (40 min.) with a lower reaction temperature (100°C, 150 W) but using 3 equivalents of
amine (entry 10).
Table 1: Selected optimization of reaction conditions under solvent-less microwave irradiations.
reaction conditions
Yield of
reaction
time
(min.)
entry product 7
starting
reagent 6
number of
equiv.
reaction
temperature (°C)
power
(Watt)
7 (%)a
1
2
7a
7a
6a
6a
2
4
30
30
40
30
50
60
15
15
30
40
155
155
155
120
120
120
100
100
100
100
300
240
240
240
240
240
150
150
150
150
30
54
58
40
67
72
16
45
77
81
3
7a
6a
4
4
7h
6h
2
5
7h
6h
2
6
7h
6h
2
7
7m
7m
7m
7m
6m
6m
6m
6m
1.5
3
8
9
3
10
3
a Isolated yield after recrystallisation.

HETEROCYCLES, Vol. 78, No. 5, 2009
1195
Having demonstrated the interest of microwave irradiation for the sulphur/nitrogen displacement using
certain primary amines 6, we sought to increase the structural diversity on the
3,4-dihydro-4H-imidazole-4-one core in order to obtain a more-diverse compounds library. For the
generality and the scope of this MAOS (microwave-assisted organic synthesis) protocol, we have
investigated the use of various aromatic primary amines differently substituted. Diversified aromatic or
aliphatic primary amines, containing a carboxylic group (6b,c) or a hydroxyl function (6d, 6k, 6l, 6n),
have been selected to widen the spectrum of biological activities of the 2-aminoimidazolone core.
Sterically hindered amine comprising a morpholine moiety (6i) has been also used in this method.
Table 2: Synthesis of leucettamine B derivatives 7a-n with various primary amines 6 using solvent-free
microwave irradiation reaction conditions.
starting reagent
reaction conditions
product
yield of
7 (%)a
structure of reagent
number of
equiv.
reaction time
reaction
7
6
6
(min.)
temperature (°C)
7a
6a
4
40
155
58
NH
2
HO2C
HO
NH2
7b
7c
6b
6c
0.9
0.9
90
90
160
160
68
74
HO C
2
NH
2
HO
NH2
NH2
7d
7e
6d
6e
2
1
45
35
160
135
69
75
O
N
O
O
NH
2
7f
6f
2
60
140
72
O
NH2
7g
7h
6g
6h
4.5
2
100
60
135
120
80
72
O
N
N
NH2
O
N
7i
7j
6i
6j
3
4
30
50
150
120
92
33
NH2
NH2
HO
OH
NH
2
7k
6k
5
40
100
64

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HETEROCYCLES, Vol. 78, No. 5, 2009
NH2
HO
7l
6l
3
3
40
40
155
100
42
81
OH
7m
6m
NH2
NH2
HO
HO
7n
6n
5
40
100
66
3
a Isolated yield after recrystallization.
Table 2 summarizes the 2-amino imidazolones synthesized as analogs of leucettamine B via this
®
solventless sulphur/nitrogen displacement under microwave irradiation by utilizing the Synthewave 402
reactor. The synthesis results of this small library showed that all 14 reactions were successful, and cleanly
generated the 2-amino-3,4-dihydro-4H-imidazole-4-ones 7a-n as confirmed by HRMS. In the majority of
cases, very high conversion and good purity of the desired products was observed. Moderate yields were
obtained (7j: 33%, 7l: 42%) when 2-amino ethanol 6j (4 equiv.) and 2,3-dihydroxy propylamine 6l (3
equiv.) were used indicating that the proportion of final product 7 between the excess of amine 6 and the
solvent for crystallization, is an important factor to maintain a good yield. The structural assignment of the
2-aminoimidazolones 7a-n is based on spectroscopic data (1H, 13C NMR). In all cases, compounds 7 were
obtained in a stereospecific way by sulphur/nitrogen displacement under microwave with retention of
stereochemistry and the geometry of the exocyclic double bond was attributed as being Z by the shielding
effect of the carbonyl C-4 on the olefinic proton H-5 (7a-n: δH-5 = 6.10-6.65 ppm).14
In summary, we have demonstrated that sulphur/nitrogen displacement is possible on a 2-ethylthio
imidazolone core with polar primary amines using a solvent-free microwave irradiation protocol. To our
knowledge, this new approach has never been reported and may be complementary to the methods
described in the literature.5b,7 Our protocol allows a stereocontrolled synthesis of leucettamine B
derivatives with a large structural diversity (fourteen new products) and in establishing fast and
inexpensive purification methodologies. The target compounds were obtained in good yields coupled to a
high purity. The biological activities of this 2-aminoimidazolones library are currently under investigation.
EXPERIMENTAL
General. Melting points were determined on a Kofler melting point apparatus and were uncorrected.
Thin-layer chromatography (TLC) was accomplished on 0.2-mm precoated plates of silica gel 60 F-254
(Merck) and visualization was made with ultraviolet light (254 and 312 nm) or with a fluorescence
1
indicator. H NMR spectra were recorded on BRUKER AC 300 P (300 MHz) and BRUKER ARX 200
13
(200 MHz) spectrometers, C NMR spectra on BRUKER AC 300 P (75 MHz) spectrometer. Chemical

HETEROCYCLES, Vol. 78, No. 5, 2009
1197
shifts are expressed in parts per million downfield from tetramethylsilane as an internal standard. Data are
given in the following order: δ value, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad), number of protons, coupling constants J is given in Hertz. The mass spectra (HRMS) were
taken on a VARIAN MAT 311 at an ionizing potential of 70 eV in the Centre Régional de Mesures
Physiques de l’Ouest (CRMPO, Rennes). Reactions under microwave irradiations were realized in the
®
Synthewave 402 apparatus (Merck Eurolab, Div. Prolabo, France). The microwave instrument consists
of a continuous focused microwave power output from 0 to 300W. All experiments were performed using
stirring option. The target temperature was reached with a ramp of 3 minutes and the chosen microwave
power remained constant to keep the mixture at this temperature. The reaction temperature is monitored
using calibrated infrared sensor and the reaction time include the ramp period. Acetonitrile was distilled
over calcium chloride after standing overnight and stored over molecular sieves (3Å). Solvents were
evaporated with a BUCHI rotary evaporator. All reagents were purchased from Acros, Aldrich Chimie,
Fluka France and used without further purification. The starting products 2, 3 and 5 were synthesized
according to our previous method.6b
General procedure for the synthesis of Leucettamine
B
derivatives 7a-n from
(5Z)-5-(1,3-benzodioxol-5-yl)methylene-3-methyl-2-ethylthio-3,4-dihydro-4H-imidazole-4-one
5
and primary amines 6 using microwave irradiations under solventless reaction conditions. A mixture
of (5Z)-5-(1,3-benzodioxol-5-yl)methylene-3-methyl-2-ethylthio-3,4-dihydro-4H-imidazole-4-one 5 (0.3
g, 1.03 mmole) and primary amine 6 (from 0.927 to 5.15 mmoles, from 0.9 to 5 equiv.) was placed in a
®
cylindrical quartz reactor (Ø = 1.8 cm). The reactor was then introduced into a Synthewave 402 Prolabo
microwave reactor (P = 300 Watt). The stirred mixture was irradiated at the appropriate reaction
temperature (see table 2 with a power level ranging from 50 to 100%) for appropriate reaction time (20-100
minutes, table 2). After microwave dielectric heating, the crude reaction mixture was allowed to cool down
at room temperature and ethanol or, diethyl ether or chloroform (10 mol) was added directly in the
cylindrical quartz reactor. The resulting precipitated product 7 was filtered off and was purified by
recrystallization from ethanol, diethyl ether or chloroform. After drying under under high vacuum (10-2
Torr) at 30 °C for 1h, the pure (5Z)-2-amino-5-(1,3-benzodioxol-5-yl)methylene-3-methyl-3,4-dihydro-
4H-imidazole-4-one 7 was characterized by 1H, 13C NMR, HRMS.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-phenylamino-3,5-dihydro-4H-imidazol-4-one
(7a): Reaction temperature: 155 °C, reaction time: 40 min. Yield = 58%. Yellow powder, mp 226-228 °C
(from Et2O). 1H NMR (300 MHz, DMSO d6) δ = 3.22 (s, 3H, CH3-N); 6.06 (s, 2H, OCH2O); 6.60 (s, 1H,
CH=); 6.95 (d, 1H, J = 8.1 Hz, H-7, Ar); 7.10 (dd, 1H, J = 7.2 Hz, J = 7.2 Hz, H-4', Ar); 7.37-7.45 (m, 3H,

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HETEROCYCLES, Vol. 78, No. 5, 2009
H-3’, H-5’, H-6, Ar); 7.91 (d, 2H, J = 6.8 Hz, H-2’, H6’, Ar); 8.00 (s, 1H, H-4, Ar); 9.40 (br s, 1H, NH). 13C
NMR (75 MHz, DMSO d6) δ = 26.1, 101.2, 108.4, 109.3, 115.9, 120.3, 123.2, 125.9, 128.6, 129.7, 137,8,
138.7, 147.3, 147.4, 154.9, 168.7. HRMS, m/z = 321.1115 found (calculated for C18H15N3O3, M+• requires
321.1113). Anal. Calcd for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.32; H, 4.75; N, 13.02.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-(3-carboxy-4-hydroxyphenyl)amino-3,5-
dihydro-4H-imidazol-4-one (7b): Reaction temperature: 160 °C, reaction time: 90 min. Yield = 68%.
Yellow powder, mp > 260 °C (from CHCl3). 1H NMR (300 MHz, DMSO d6) δ = 3.22 (s, 3H, CH3-N); 6.06
(s, 2H, OCH2O); 6.59 (s, 1H, CH=); 6.93-7.00 (m, 2H, H-7, H-5’, Ar); 7.70-7.74 (m, 2H, H-4, H-6, Ar);
7.85 (d, 1H, J = 7.9 Hz, H-6’, Ar); 8.76 (s, 1H, H-2’, Ar); 9.40 (br s, 1H, NH); 11.50 (br s, 2H, CO2H, OH).
13C NMR (75 MHz, DMSO d6) δ = 26.0, 101.1, 108.4, 109.9, 112.4, 115.6, 117.1, 121.3, 125.5, 128.0,
129.6, 130.5, 137.6, 147.2, 147.3, 154.7, 157.1, 168.6, 171.9. HRMS, m/z = 382.1036 found (calculated for
C19H15N3O6, M+• requires 382.1039). Anal. Calcd for C19H15N3O6: C, 59.84; H, 3.96; N, 11.02. Found: C,
59.86; H. 3.93; N, 11.07.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-(4-carboxymethylphenyl)amino-3,5-dihydro-
4H-imidazol-4-one (7c): Reaction temperature: 160 °C, reaction time: 90 min. Yield = 74%. Yellowish
powder, mp 262-264 °C (from CHCl3). 1H NMR (300 MHz, DMSO d6) δ = 3.21 (s, 3H, CH3-N); 3.57 (s,
2H, CH2CO2H); 6.06 (s, 2H, OCH2O); 6.58 (s, 1H, CH=); 6.96 (m, 1H, H-7, Ar); 7.30 (m, 2H, H-3', H-5',
Ar); 7.41 (m, 1H, H-6, Ar); 7.87 (m, 2H, H-2', H-6', Ar); 7.99 (s, 1H, H-4, Ar); 9.38 (br s, 1H, NH); 12.20
(br s, 1H, CO2H). 13C NMR (75 MHz, DMSO d6) δ = 26.1, 40.2, 101.2, 108.4, 109.3, 115.9, 120.0, 125.8,
129.5, 129.7, 129.8, 137.3, 137.8, 147.3, 147.4, 154.9, 168.7, 172.80. HRMS, m/z = 379.1156 found
(calculated for C20H17N3O5, M+• requires 379.1168). Anal. Calcd for C20H17N3O5: C, 63.32; H, 4.52; N,
11.08. Found: C, 63.37; H, 4.55; N, 11.06.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-[4-(2-hydroxyethyl)phenyl]amino-3,5-
dihydro-4H-imidazol-4-one (7d): Reaction temperature: 160 °C, reaction time: 45 min. Yield = 69%.
Yellow powder, mp 210-212 °C (from EtOH). 1H NMR (300 MHz, DMSO d6) δ = 2.73 (t, 2H, J = 6.0 Hz,
ArCH2CH2OH); 3.21 (s, 3H, CH3-N); 3.63 (m, 2H, ArCH2CH2OH); 4.66 (br s, 1H, OH); 6.06 (s, 2H,
OCH2O); 6.57 (s, 1H, CH=); 6.95 (d, 1H, J = 8.0 Hz, H-7, Ar); 7.24 (d, 2H, J = 7.6 Hz, H-3', H-5', Ar); 7.43
(d, 1H, J = 8.0 Hz, H-6, Ar); 7.82 (d, 2H, J = 7.6 Hz, H-2', H-6', Ar); 7.98 (s, 1H, H-4, Ar); 9.32 (br s, 1H,
NH). 13C NMR (75 MHz, DMSO d6) δ = 26.6, 38.9, 62.6, 101.7, 108.9, 109.8, 116.2, 120.5, 126.3, 129.5,
130.3, 135.0, 137.1, 138.4, 147.8, 147.9, 155.4, 169.2. HRMS, m/z = 365.1364 found (calculated for
C20H19N3O4, M+• requires 365.1376). Anal. Calcd for C20H19N3O4: C, 65.74; H, 5.24; N, 11.50. Found: C,

HETEROCYCLES, Vol. 78, No. 5, 2009
1199
65.76; H, 5.22; N, 11.51.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-[4-(N-morpholinyl)phenyl]amino-3,5-
dihydro-4H-imidazol-4-one (7e): Reaction temperature: 135 °C, reaction time: 35 min. Yield = 75%.
1
Yellow powder, mp > 260 °C (from EtOH). H NMR (300 MHz, DMSO d6) δ =3.10 (m, 4H,
N(CH2CH2)2O); 3.20 (s, 3H, CH3-N); 3.75 (s, 4H, N(CH2CH2)2O); 6.05 (s, 2H, OCH2O); 6.52 (s, 1H,
CH=); 6.94 (d, 1H, J = 8.0 Hz, H-7, Ar); 6.97 (d, 2H, J = 8.6 Hz, H-3', H-5', Ar); 7.44 (d, 1H, J = 8.0 Hz,
H-6, Ar); 7.76 (d, 2H, J = 8.6 Hz, H-2', H-6', Ar); 7.94 (s, 1H, H-4, Ar); 9.22 (br s, 1H, NH). 13C NMR (75
MHz, DMSO d6) δ = 26.5, 49.2, 66.6, 101.6, 108.9, 109.8, 115.4, 115.7, 121.9, 126.1, 130.4, 131.1, 138.6,
147.6, 147.7, 147.8, 155.4, 169.3. HRMS, m/z = 406.1662 found (calculated for C22H22N4O4, M+• requires
406.1641). Anal. Calcd for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C, 65.03; H, 5.50; N, 13.74.
(5Z)-2-[(1,3-Benzodioxol-5-yl)methylamino]-5-[(1,3-benzodioxol-5-yl)methylene]-3-methyl-3,5-
dihydro-4H-imidazol-4-one (7f): Reaction temperature: 140 °C, reaction time: 60 min. Yield = 72%.
Yellow powder, mp 202-204 °C (from EtOH). 1H NMR (300 MHz, DMSO d6) δ = 3.07 (s, 3H, CH3-N);
4.53 (d, 2H, J = 5.0 Hz, CH2NH); 5.98 (s, 2H, OCH2O); 6.02 (s, 2H, OCH2O); 6.40 (s, 1H, CH=);
6.86-6.92 (m, 3H, H-7, H-6’, H-7’, Ar); 7.02 (s, 1H, H-4', Ar); 7.42 (d, 1H, J = 7.4 Hz, H-6, Ar); 7.97 (s,
1H, H-4, Ar); 8.17 (t, 1H, J = 5.0 Hz, NH). 13C NMR (75 MHz, DMSO d6) δ = 25.5, 44.3, 100.8, 101.0,
107.9, 108.2, 108.3, 109.4, 113.1, 121.0, 125.2, 130.3, 132.8, 138.7, 146.3, 146.7, 147.2, 158.0, 169.5.
HRMS, m/z = 379.1156 found (calculated for C20H17N3O5, M+• requires 379.1169). Anal. Calcd for
C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found: C, 63.35; H, 4.57; N, 11.07.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-[(2,2-dimethoxy)ethylamino]-3,5-dihydro-4H-
imidazol-4-one (7g): Reaction temperature: 135 °C, reaction time: 100 min. Yield = 80%. Yellow powder,
1
mp 184-186 °C (from EtOH). H NMR (300 MHz, DMSO d6) δ = 3.05 (s, 3H, CH3-N); 3.40 (s, 6H,
2(OCH3)); 3.50 (dd, 2H, J = 4.5, 5.1 Hz, CH2NH); 4.68 (t, 1H, J = 5.1 Hz, CH(OMe)2); 6.02 (s, 2H,
OCH2O); 6.40 (s, 1H, CH=); 6.89 (d, 1H, J = 8.1 Hz, H-7, Ar); 7.37 (d, 1H, J = 8.1 Hz, H-6, Ar); 7.84 (t,
1H, J = 4.5 Hz, NH); 8.01 (s, 1H, H-4, Ar). 13C NMR (75 MHz, DMSO d6) δ = 25.2, 43.2, 54.8, 101.1,
102.4, 108.3, 110.3, 117.4, 126.2, 130.1, 137.8, 147.7, 148.3, 157.2, 170.2. HRMS, m/z = 333.1339 found
(calculated for C16H19N3O5, M+• requires 333.1325). Anal. Calcd for C16H19N3O5: C, 57.65; H, 5.75; N,
12.61. Found: C, 57.71; H, 5.79; N, 12.58.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-2-[(imidazol-1-yl)propylamino]-3-methyl-3,5-dihydro-
4H-imidazol-4-one (7h): Reaction temperature: 120 °C, reaction time: 60 min. Yield = 72%. Yellow

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HETEROCYCLES, Vol. 78, No. 5, 2009
powder, mp 202-204 °C (from CHCl3). 1H NMR (300 MHz, DMSO d6) δ = 2.10 (m, 2H, CH2CH2CH2);
3.04 (s, 3H, CH3-N); 3.42 (m, 2H, CH2NH); 4.08 (t, 2H, J = 6.7 Hz, CH2N); 6.03 (s, 2H, OCH2O); 6.38 (s,
1H, CH=); 6.89-6.93 (m, 2H,, H-7, NCH=C, Ar); 7.23 (s, 1H, NCH=N, Ar); 7.41 (d, 1H, J = 8.2 Hz, H-6,
Ar); 7.67-7.70 (m, 2H, NCH=C, NH); 7.92 (s, 1H, H-4, Ar). 13C NMR (75 MHz, DMSO d6) δ = 25.5, 30.2,
38.4, 43.6, 101.0, 108.3, 109.5, 113.0, 119.3, 125.2, 128.4, 130.3, 137.3, 138.7, 146.7, 147.2, 158.1, 169.5.
HRMS, m/z = 353.1482 found (calculated for C18H19N5O3, M+• requires 353.1488). Anal. Calcd for
C18H19N5O3: C, 61.18; H, 5.42; N, 19.82. Found: C, 61.25; H, 5.45; N, 19.77.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-3-methyl-2-[(morpholin-1-yl)ethylamino]-3,5-dihydro-
4H-imidazol-4-one (7i): Reaction temperature: 150 °C, reaction time: 30 min. Yield = 92%. Brown
powder, mp 182-184 °C (from Et2O). 1H NMR (300 MHz, CDCl3) δ = 2.57 (m, 4H, N(CH2CH2)2O); 2.71
(m, 2H, NHCH2CH2N); 3.13 (s, 3H, CH3-N); 3.67 (t, 2H, J = 5.1 Hz, NHCH2CH2N); 3.74 (m, 4H,
N(CH2CH2)2O); 5.97 (s, 2H, OCH2O); 6.64 (s, 1H, CH=); 6.80 (d, 1H, J = 6.8 Hz, H-7, Ar); 7.32 (d, 1H, J
= 6.8 Hz, H-6, Ar); 7.98 (s, 1H, H-4, Ar); NH not detected. 13C NMR (75 MHz, CDCl3) δ = 25.2, 37.5, 53.2,
56.6, 66.8, 100.1, 108.3, 110.2, 117.0, 126.1, 130.2, 138.0, 147.6, 147.7, 157.1, 170.2. HRMS, m/z =
358.1645 found (calculated for C18H22N4O4, M+• requires 358.1641). Anal. Calcd for C18H22N4O4: C,
60.32; H, 6.19; N, 15.63. Found: C, 60.33; H, 6.22; N, 15.62.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-2-[(2-hydroxyethyl)amino]-3-methyl-3,5-dihydro-4H-
imidazol-4-one (7j): Reaction temperature: 120 °C, reaction time: 50 min. Yield = 33%. Yellow powder,
1
mp 180-182 °C (from EtOH). H NMR (300 MHz, DMSO d6) δ = 3.05 (s, 3H, CH3-N); 3.49 (s, 2H,
CH2OH); 3.64 (s, 2H, CH2NH); 4.87 (br s, 1H, OH); 6.02 (s, 2H, OCH2O); 6.36 (s, 1H, CH=); 6.90 (d, 1H,
J = 7.0 Hz, H-7, Ar); 7.34 (d, 1H, J = 7.0 Hz, H-6, Ar); 7.66 (br s, 1H, NH); 7.94 (s, 1H, H-4, Ar). 13C NMR
(75 MHz, DMSO d6) δ = 25.5, 43.9, 59.3, 100.9, 108.2, 109.4, 112.7, 125.1, 130.3, 138.7, 146.6, 147.1,
158.2, 169.51. HRMS, m/z = 289.1055 found (calculated for C14H15N3O4, M+• requires 289.1063). Anal.
Calcd for C14H15N3O4: C, 58.13; H, 5.23; N, 14.53. Found: C, 58.19; H, 5.20; N; 14.55.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-2-[(2-hydroxypropyl)amino]-3-methyl-3,5-dihydro-4H-
imidazol-4-one (7k): Reaction temperature: 155 °C, reaction time: 40 min. Yield = 64%. Yellow powder,
mp 208-210 °C (from EtOH). 1H NMR (300MHz, DMSO d6) δ = 1.13 (d, 3H, J = 6.2 Hz, CH3CHOH);
3.07 (s, 3H, CH3-N); 3.34 (m, 2H, CHCH2NH); 3.97 (m, 1H, CH3CHOH); 4.93 (br s, 1H, OH); 6.03 (s, 2H,
OCH2O); 6.37 (s, 1H, CH=); 6.90 (d, 1H, J = 8.1 Hz, H-7, Ar); 7.38 (dd, 1H, J = 1.0, 8.1 Hz, H-6, Ar); 7.65
(br s, 1H, NH ); 7.96 (d, 1H, J = 1.0 Hz, H-4, Ar). 13C NMR (75 MHz, DMSO d6) δ = 21.1, 25.5, 48.9, 64.8,
101.0, 108.2, 109.4, 112.7, 125.1, 130.3, 138.7, 146.6, 147.2, 158.3, 169.5. HRMS, m/z = 303.1223 found

HETEROCYCLES, Vol. 78, No. 5, 2009
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(calculated for C15H17N3O4, M+• requires 303.1219). Anal. Calcd for C15H17N3O4: C, 59.40; H, 5.65; N,
13.85. Found: C, 59.37; H, 5.62; N, 13.82.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-2-[(2,3-hydroxypropyl)amino]-3-methyl-3,5-dihydro-4H-
imidazol-4-one (7l): Reaction temperature: 155 °C, reaction time: 40 min. Yield = 42%. Yellow powder,
1
mp 128-130°C (from EtOH). H NMR (300 MHz, DMSO d6) δ = 3.06 (s, 3H, CH3N); 3.39 (m, 3H,
CH2OH, CH2NH); 3.53 (m, 1H, CHOH); 3.76 (m, 1H, CH2NH); 4.74 (t, 1H, J = 5.7 Hz, OH); 5.03 (d, 1H,
J = 4.7 Hz, OH); 6.03 (s, 2H, OCH2O); 6.37 (s, 1H, CH=); 6.91 (d, 1H, J = 8.0 Hz, H-7, Ar); 7.37 (d, 1H, J
= 8.0 Hz, H-6, Ar); 7.68 (br s, 1H, NH); 7.88 (s, 1H, H-4, Ar). 13C NMR (75 MHz, DMSO d6) δ = 25.5,
44.7, 63.5, 70.2, 101.0, 108.3, 109.4, 112.8, 125.2, 130.2, 138.4, 146.7, 147.2, 158.5, 169.4. HRMS, m/z =
319.1176 found (calculated for C15H17N3O5, M+• requires 319.1168). Anal. Calcd for C15H17N3O5: C,
56.42; H, 5.37; N, 13.16. Found: C, 56.40; H, 5.41; N, 13.15.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-2-[(3-hydroxypropyl)amino]-3-methyl-3,5-dihydro-4H-
imidazol-4-one (7m): Reaction temperature: 100 °C, reaction time: 40 min. Yield = 81%. Yellow powder,
1
mp 198-200 °C (from EtOH). H NMR (300 MHz, DMSO d6) δ = 1.81 (tt, 2H, J = 6.5, 6.5 Hz,
CH2CH2CH2); 3.04 (s, 3H, CH3-N); 3.47-3.53 (m, 4H, HOCH2CH2CH2NH); 4.60 (br s, 1H, OH); 6.02 (s,
2H, OCH2O); 6.37 (s, 1H, CH=); 6.90 (d, 1H, J = 8.2 Hz, H-7, Ar); 7.38 (dd, J = 1.3, 8.2 Hz, H-6, Ar); 7.60
(br s, 1H, NH ); 7.95 (d, 1H, J = 1.3 Hz, H-4, Ar). 13C NMR (75 MHz, DMSO d6) δ = 25.4, 32.0, 38.4, 58.3,
101.0, 108.2, 109.4, 112.7, 125.1, 130.3, 138.8, 146.6, 147.2, 158.0, 169.5. HRMS, m/z = 303.1196 found
(calculated for C15H17N3O4, M+• requires 303.1219). Anal. Calcd for C15H17N3O4: C, 59.40; H, 5.65; N,
13.85. Found: C, 59.48; H, 5.63; N, 13.79.
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-2-[(5-hydroxypentyl)amino]-3-methyl-3,5-dihydro-4H-
imidazol-4-one (7n): Reaction temperature: 100 °C, reaction time: 40 min. Yield = 66%. Yellow powder,
mp 148-150 °C (from Et2O). 1H NMR (300 MHz, DMSO d6) δ = 1.35-1.70 (m, 6H,
HOCH2(CH2)3CH2NH); 3.04 (s, 3H, CH3-N); 3.41 (m, 4H, HOCH2(CH2)3CH2NH); 4.38 (br s, 1H, OH);
6.02 (s, 2H, OCH2O); 6.35 (s, 1H, CH=); 6.90 (d, 1H, J = 8.1 Hz, H-7, Ar); 7.40 (dd, J = 1.2, 8.1 Hz, H-6,
Ar); 7.62 (br s, 1H, NH); 7.96 (d, 1H, J = 1.2 Hz, H-4, Ar). 13C NMR (75 MHz, DMSO d6) δ = 23.0, 25.4,
28.6, 32.1, 41.2, 60.6, 101.0, 108.2, 109.4, 112.5, 125.1, 130.4, 139.0, 146.6, 147.1, 158.0, 169.5. HRMS,
m/z = 331.1537 found (calculated for C17H21N3O4, M+• requires 331.1532). Anal. Calcd for C17H21N3O4: C,
61.12; H, 6.39; N, 12.68. Found: C, 61.16; H, 6.37; N, 12.59.

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ACKNOWLEDGEMENTS
We thank the “Conseil Régional de Bretagne: Programme 1042” for a research fellowship (contract
N°2004 6919 for S.R.) and the "Ministère de l'Enseignement Supérieur et de la Recherche Scientifique de
la République Algérienne Démocratique et Populaire (Coopération et Echanges Interuniversitaires
Franco-Algérien CMEP for M.D.). The work presented here was supported by the Cancéropôle
Grand-Ouest. LM’s funding includes CRITT Santé Bretagne, Fondation Jérôme Lejeune and Fondation
France Alzheimer (Finistère, France). We also thank Merck Eurolab Prolabo (Fr.) for providing the
®
Synthewave 402 apparatus.
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