A practical approach to new (5Z) 2-alkylthio-5-arylmethylene-1-methyl-1,5- dihydro-4H-imidazol-4-one derivatives

Article abstract of DOI:10.3390/molecules16097377

A practical protocol for the preparation of (5Z)-2-alkylthio-5- arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one derivatives is reported. The new compounds were obtained in good yield and stereoselectivity in two steps, namely a solvent-free Knoevenag

Full text of DOI:10.3390/molecules16097377

Molecules 2011, 16, 7377-7390; doi:10.3390/molecules16097377
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Practical Approach to New (5Z) 2-Alkylthio-5-arylmethylene-
1-methyl-1,5-dihydro-4H-imidazol-4-one Derivatives
Khadidja Bourahla 1, Ludovic Paquin 1, Olivier Lozach 2, Laurent Meijer 2, François Carreaux 1
and Jean Pierre Bazureau 1,*
1
Chemical Engineering & Molecules for Life Sciences Group, Université de Rennes 1,
Sciences Chimiques de Rennes (SCR), UMR CNRS 6226, Bât. 10A, Campus de Beaulieu,
Avenue du Général Leclerc, CS 74205, 35042 Rennes Cedex, France
2
Protein Phosphorylation and Human Disease Group, Station Biologique CNRS, Place G. Tessier,
BP 74, 29682 Roscoff, France
* Author to whom correspondence should be addressed; E-Mail: jean-pierre.bazureau@univ-rennes1.fr;
Tel.: +33 (0)223 236 603; Fax: +33 (0)223 236 374.
Received: 13 July 2011; in revised form: 25 August 2011 / Accepted: 22 August 2011 /
Published: 30 August 2011
Abstract: A practical protocol for the preparation of (5Z)-2-alkylthio-5-arylmethylene-1-
methyl-1,5-dihydro-4H-imidazol-4-one derivatives is reported. The new compounds were
obtained in good yield and stereoselectivity in two steps, namely a solvent-free
Knoevenagel condensation under microwave irradiation, followed by an S-alkylation
reaction with various halogenoalkanes.
Keywords: 1,5-dihydro-4H-imidazol-4one; Knoevenagel condensation; microwave
irradiation; S-alkylation
1. Introduction
2-Thiohydantoins (4-oxoimidazolidine-2-thiones) [1,2] and their 2-alkylthio-3,5-dihydro-4H-
imidazol-4-one derivatives are a biologically important class of compounds in the fields of drugs,
pharmaceutical intermediates and agrochemicals. As examples, the isatinylidene derivative I (Figure 1)
exhibits immunosuppressive activity [3] and the thioglycosyl hydantoin [4] II possesses a broad
spectrum antitumor activity against a wide range of different human cell lines from nine tumor

Molecules 2011, 16
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subpanels causing both cytostatic and cytotoxic effects. The 5-arylmethylene-2-methylthio-imidazol-4-
ones III substituted with a biphenyltetrazole (BTP) group at the C-2 position show activities as
angiotensin II receptor antagonists [5] and the 3-morpholinomethyl-5,5-dimethyl-2-thioglycosyl-
imidazol-4-one IV has been also identified as a potential AZT analogue [6]. The 2-thiohydantoin
derivatives have not only been used in medicinal chemistry, but have also been developed as
fungicides [7] [e.g., fenamidone (V) [8,9]] and herbicides [10]. Recent work [11] by Wang's group has
established that esters of 5-(4-hydroxybenzyl)thiohydantoins exhibit good herbicidal activity against
Zea mays and Arabidopsis thaliana.
Figure 1. Select 3,5-dihydro-4H-imidazol-4-one derivatives with biological activities.
OAc
N
N
OAc
O
NH
R2S
O
AcO
AcO
O
N
N
S
R1
AcO
AcO
Br
N
S
N
S
OAc
Me
Me
N
N
N
OAc
S
R
N
N
O
N
O
R
N
O
O
II
III: (R = Me, Et)
IV
I
O
R1
R2S
MeS
N
N
Ar
N
Me
N
HN
O
O
V
VI
On the other hand, the synthesis and biological properties of 2-alkylthio-5-arylmethylene-1,5-
dihydro-4H-imidazol-4-one derivatives VI have rarely been the subject of detailed investigations
reported in the literature. A 17-year-old study of Unangst and co-workers only reported the preparation
of (5Z)-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-methylthio-
4H-imidazol-4-one for an inflammation therapy program [12]. In 1993, a report described the
biological activity of the same compound as a potent antiviral agent for the human immunodeficiency
virus (HIV) [13]. More recently, the use of 5-arylidene-1-methyl-1,5-dihydro-4H-imidazol-4-one as
a convenient synthetic intermediate in a sulfur/nitrogen displacement has been studied with one
example [14].
Due to the biological activity associated with the imidazolone moiety, we embarked on a project to
investigate possible bioactive molecules based on 2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-
4H-imidazol-4-one derivatives of the imidazolone core. Herein, we report our results concerning the
synthesis of these new 2-alkylthio-5-arylmethylene derivatives based on the 1-methyl-2-thiohydantoin
scaffold and their biological evaluation as protein kinase inhibitors. The protein kinases of the human
kinome represent a wide family of disease relevant targets for identification, preparation and
optimization of potential therapeutic agents in structure-activity relationship (SAR) studies [15].
2. Results and Discussion
Most of the 2-alkylthio-5-arylmethylene imidazol-4-ones syntheses described in the literature
involve: (i) a Knoevenagel condensation of an aryl/heteroaryl aldehyde with a 2-thiohydantoin
followed by a regioselective S-alkylation [16] or (ii) reaction of vinylisothiocyanate [17] (obtained

Molecules 2011, 16
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from an iminophosphorane [18] and carbon disulfide) with a primary amine giving the
5-arylmethylene-2-thioxo-imidazol-4-one structure [19,20], which is then converted into the S-alkyl
derivative by the action of an alkylating reagent.
For this project, the needed 2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one
can be built from sarcosine and a thiocyanate as precursors of the 1-methyl-2-thiohydantoin scaffold,
aldehydes and halogenoalkanes, to introduce diversity at the C-5 position and on the sulfur atom at the
C-2 position respectively, by Knoevenagel condensation and S-alkylation reactions (Figure 2).
Figure 2. Components used for the synthesis of 2-alkylthio-5-arylmethylene-1-methyl-1,5-
dihydro-4H-imidazol-4-ones.
Ar
O
Me
Me
R2S
aldehyde
O
S
H
N
N
H
Ar
N
N=C=S
OH
sarcosine
N
N
R2 X
thiocyanate
O
O
halogeno
alkane
1-methyl-2-thio
hydantoine
As illustrated in Scheme 1, the synthesis started with the preparation of 1-methyl-2-thiohydantoin
(1) from commercially available sarcosine and ammonium thiocyanate.
Scheme 1. Route used for the synthesis of 2-alkylthio-5-arylmethylene-1-methyl-1,5-
dihydro-4H-imidazol-4-ones.
Me
Me
Me
RS
S
H
S
H
Ar
Ar
N
N
N
Me
OH
i
ii
iii
N
H
N
N
N
R X
O
Ar
or
2
O
O
O
O
sarcosine
1
4
5
6
3
Ar
N
Reagent and reaction conditions: (i) NH4SCN (3 equiv.), 140 °C, 19 h. (ii) Method A: 2 (1 equiv.),
propylamine (2 equiv.), μω, 80 °C, 40-60 min. or Method B: 3 (1 equiv.), μω, 80 °C, 40-60 min.
(iii) 5 (1-1.5 equiv.), K2CO3 (0.5 equiv.), KI (1 equiv.), MeCN, 60-81 °C, 19-51 h.
Complete conversion according to the modified procedure of Kenyon et al. [21,22] was observed
after 19 hours at 140 °C, affording the desired starting compound 1 in 90% yield. In the second step,
for the Knoevenagel condensations from aryl aldehydes and thiohydantoins, several methods have
been employed in the literature. Many of these methods suffer from one or more limitations such as
requiring harsh reaction conditions, producing low to moderate yields, relatively long reaction times
and cumbersome experimental processes. Among these reported methods, the Knoevenagel reaction
has been performed in the presence of mineral or organic bases with various solvents: ethanolamine in
absolute ethanol [23], potassium hydroxide in anhydrous ethanol [24], sodium hydride in anhydrous
acetonitrile [25]. The utility of microwave irradiation (μω) to carry out organic reaction has now
become a regular feature. The main benefits of performing the reaction under microwave conditions
are the higher product yields and the significant rate-enhancements that can be observed. It’s clear that

Molecules 2011, 16
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application of microwave technology to the rapid synthesis of potential biological molecules is a useful
tool for the medicinal chemistry community, for whom reaction speed is of great importance [26,27].
Moreover, when a reaction is carried out in a microwave reactor, the use of solvent can be
avoided [28,29], allowing eco-friendly synthesis and offering several advantages, such as reduced risk of
explosions and easier work-up. In this context, we have examined two experimental protocols for the
synthesis of 5-arylmethylene-1-methyl-2-thiohydantoins 4.
The results of the two methods investigated for the preparation of Knoevenagel products 4 are
presented in Table 1. In Method A, 1-methyl-2-thiohydantoin (1) was coupled with commercial aryl
aldehydes 2(a-e) in the presence of two equivalents of propylamine at 80 °C under microwave
irradiation (in a Synthewave® 402 reactor [30]) for a reaction time ranging from 40 to 60 minutes. In
Method B, an equimolecular mixture of the starting hydantoin 1 and arylaldimine 3 was heated at
80 °C under microwave irradiation for the same reaction time. The arylaldimines 3 were prepared in
good yields according to a solvent-free microwave protocol developed in our laboratory [31]. The
reactions of both methods were conveniently monitored by 1H- NMR or by TLC on precoated plates of
silica gel with an appropriate eluant. As can be seen from inspection of the data presented in Table 1,
the 5-arylmethylene-1-methyl- 2-thioxo-imidazolidin-4-ones 4(a-e) were prepared in better yields
(86-98%) using the microwave irradiation reaction conditions (Method A). It is noteworthy that for
safety reasons, a 4-min. heating ramp was performed before the temperature was maintained at the
selected maximum of 80 °C (power 80 W). The structure of the new compounds 4(a-e) were
1
substantiated by H-, 13C-NMR and HRMS. In all cases, compounds 4 were obtained in a
stereospecific way and the geometry of the double bond was attributed as being Z by the shielding
effect of the carbonyl group C-4 on the olefinic proton H-5 (δH-5 = 6.34-6.85 ppm) [32,33].
Table 1. Results for the solvent-less preparation of 5-arylmethylene-1-methyl-2-thioxo
imidazolin-4-ones 4(a-e) under microwave from aldehydes 2(a-e) (Method A) or aldimines
3(a-e) (Method B).
Method A
Starting reagent
Method B
Starting reagent
Product
Yield a of 4 (%)
Yield a of 4 (%)
4a
4b
4c
4d
4e
2a
2b
2c
2d
2e
96
96
90
86
98
3a
3b
3c
3d
3e
88
92
90
-
92
b
O
O
O
O
HO
O
O
O
O
O
O
O
O
O
O
2b
2c
2d
2e
2a
a
b
Yield of isolated product after purification by recrystallization; The reaction failed under
microwave and also in an oil bath using the same reaction conditions.
With the 5-arylmethylene-1-methyl-2-thioxo imidazolin-4-one derivatives 4 in hand, we designed
an experimental strategy for the preparation of the 2-alkylthio-1,5-dihydro-4H-imidazol-4-ones 6. For
this study, a set of different halogeno compounds 5 represents the second point of diversity in this

Molecules 2011, 16
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scaffold by using commercial products [ethyl iodide (5a), allyl bromide (5b), propyl bromide (5c),
chloroacetonitrile (5d), ethyl bromoacetate (5e) and 3-bromopropanol (5f)]. Owing to the lesser
reactivity of the chloro and bromo alkanes 5(b-f), one equivalent of potassium iodide was added in the
reaction mixtures and the reagents were covered with dry acetonitrile. After work-up (elimination of
the salts and solvent), all the crude products were purified easily by recrystallization in ethanol. The
reaction conditions listed in Table 2 showed that the S-alkylations could be carried out at various
reaction temperatures (60-81 °C) with a reaction time ranging from 14 to 51 hours. As seen from the
results, it can be observed that these S-alkylations gave moderate to good yields (42-68%). The
structural assignment of the new 2-alkylthio-5-arylmethylene-1-methyl 1,5-dihydro-4H-imidazol-4-
ones 6(a-g) is based on spectroscopic data (1H-, 13C-NMR, HRMS). It should be noted that
this alkylation step gave regioselective S-alkylation with retention of the (5Z)-stereochemistry
(δH-5 = 6.83-7.21 ppm).
The (5Z) 2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-ones 6(a-g) were next
tested for their potential inhibitory action on two protein kinases, CDK1/cyclin B and GSK-3α/β.
Kinases were purified and essayed in the presence of 15 mM ATP and appropriate protein substrates
(histone H1 for CDK1/cyclin B, GS-1 peptide for GSK-3α/β) as previously described [34-36].
Investigation of in-vitro bioactivity revealed that none of the compounds 6(a-g) was active
(IC50 > 10 μM).
Table 2. Results for the preparation of (5Z)-2-alkylthio-5-arylmethylene-1-methyl 1,5-
dihydro-4H-imidazol-4-one 6(a-e) from (5Z)-5-arylmethylene-1-methyl-2-thioxo imidazol-
in-4-ones 4 and halogeno alkanes 5.
Reaction
Starting
product 4
conditions:
temperature a
and reaction time
60 °C, 51 h
Yield b
of 6 (%)
Product 6
R
Reagent 5
6a
6b
6c
6d
6e
6f
CH3CH2
CH2=CH-CH2
CH3CH2CH2
NC-CH2
EtO2C-CH2
EtO2C-CH2
HOCH2CH2CH2
4a
4a
4a
4a
4a
4b
4a
5a
5b
5c
5d
5e
5e
5f
60
65
62
66
68
62
42
66 °C, 48 h
65 °C, 24 h
81 °C, 19h
60 °C, 14 h
60 °C, 19 h
70 °C, 46 h
6g
O
Br
Br
Br
Cl
I
HO
Br
N
O
5a
5c
5e
5b
5d
5f
a
b
Reactions were run in a thermostated oil bath, temperature variation ±1 °C; Yield of isolated
product after purification by recrystallization.

Molecules 2011, 16
7382
3. Experimental
3.1. General
Melting points were determined on a Kofler melting point apparatus and are 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
13
fluorescent indicator. 1H- and C-NMR spectra were recorded on a Bruker AC 300 P spectrometer at
300 MHz and 75 MHz, respectively. Chemical shifts are expressed in parts per million downfield from
tetramethylsilane as an internal standard. Data are given in the following order: d 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 respectively on a Varian MAT 311 at an
ionizing potential of 70 eV in the Centre Régional de Mesures Physiques de l’Ouest (CRMPO,
Rennes, France). 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 the experiments were performed using stirring
option. The target temperature was reached with a ramp of 4 minutes and the chosen microwave power
stay constant to hold the mixture at this temperature. The reaction temperature is monitored using
calibrated infrared sensor and the reaction time includes the ramp period. Acetonitrile was distilled
over calcium chloride after standing overnight and stored over molecular sieves (3Å). Solvents were
evaporated with a Büchi rotary evaporator. All reagents were purchased from Acros, Aldrich Chimie,
Fluka France and used without further purification.
1-Methyl-2-thioxo imidazolidin-4-one (1): This starting compound was prepared in a 50 mL two-
necked round-bottomed flask, equipped with a magnetic stirrer and reflux condenser by the fusion of
commercial sarcosine (4 g, 44.9 mmol) with ammonium thiocyanate NH4SCN (10.26 g, 134.7 mmol,
3 equiv.) at 140 °C under a slow stream of nitrogen. After 19 hr of heating under vigorous stirring, the
dark red solution was cooled. The solid cake which formed was broken up and washed with 20 mL of
water onto a filter. The crystals were then washed successively with deionized water (three 15 mL
portions), 95% ethanol (one 20 mL portion) and hexane (one 20 mL portion). The precipitated product
was further dried under high vacuum (10−2 Torr) at 30 °C for 2 hours, to give the desired 1-methyl-2-
thioxoimidazolidin-4-one (1) as a powder that was used without further purification. Yield = 90%.
1
Mp = 230-232 °C. H-NMR [(CD3)2SO] δ = 3.12 (s, 3H, NCH3); 4.20 (s, 2H, CH2); 11.67 (br s, 1H,
13
NH). C-NMR [(CD3)2SO] δ = 33.3 (NCH3); 55.7 (CH2, C-5); 172.7 (C=O, C-4); 182.0 (C=S, C-2).
HRMS, m/z found: 130.0207 (calculated for C4H6N2OS, M+. requires: 130.0201).
3.2. General Procedure for the Solventless Synthesis of (5Z) 5-Arylmethylene-1-methyl-2-thioxo-
imidazolin-4-ones 4 under Microwave Dielectric Heating according to Method A and Method B:
Method A: A mixture of 1-methyl-2-thioxo-imidazolidin-4-one (1, 1.3 g, 10 mmol), propylamine
(1.64 mL, 20 mmol, 2 equiv.) and appropriate aromatic aldehyde 2 (10 mmol) was placed in a
cylindrical quartz reactor (Ø = 2.8 cm). The reactor was then introduced into a Synthewave® 402
Prolabo microwave reactor (P = 300 Watt). The stirred mixture was irradiated at 80 °C (with a power

Molecules 2011, 16
7383
of 90 Watt) for 40-60 min. After microwave dielectric heating, the crude reaction mixture was allowed
to cool down at room temperature and was concentrated by rotary evaporation under reduced pressure.
Ethanol (10 mL) was added directly in the crude reaction mixture and the resulting precipitated crude
product 4 was filtered off and purified by recrystallization from ethanol to give the desired (5Z)
5-arylmethylene-1-methyl-2-thioxo-imidazolin-4-one 4.
Method B: A mixture of 1-methyl-2-thioxo-imidazolidin-4-one (1, 1.3 g, 10 mmol) and an appropriate
aldimine 3 (10 mmol) was placed in a cylindrical quartz reactor (Ø = 2.8 cm). The reactor was then
introduced into a Synthewave® 402 Prolabo microwave reactor (P = 300 Watt). The stirred mixture
was irradiated at 80 °C (with a power of 90 Watt) for 40-60 min. After microwave dielectric heating,
the crude reaction mixture was allowed to cool down at room temperature and was concentrated by
rotary evaporation under reduced pressure. Ethanol (10 mL) was added directly in the crude reaction
mixture and the resulting precipitated crude product 4 was filtered off and purified by recrystallization
from ethanol to give the desired (5Z) 5-arylmethylene-1-methyl-2-thioxo-imidazolin-4-one 4.
(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-1-methyl-2-thioxoimidazolidin-4-one (4a): Method A: The
product 4a was prepared from 1 (1.3 g, 10 mmol), propylamine (1.64 mL, 20 mmol, 2 equiv.) and
piperonal (2a, 1.502 g, 10 mmol) with a reaction of 50 min. Yield = 96%.
Method B: The product 4a was prepared from 1 (650 mg, 5 mmol) and N-(1,3-benzodioxol-5-
ylmethylene)propan-1-amine (3a, 630 mg, 5 mmol) with a reaction time 60 min. Yield = 88%.
1
Yellow needles, mp = 252-254 °C. H-NMR [(CD3)2SO] δ = 3.18 (s, 3H, NCH3); 6.09 (s, 2H,
OCH2O); 6.54 (s, 1H, C=CH); 6.96 (d, 1H, J = 8.1 Hz, H-5', Ar); 7.27 (d, 1H, J = 8.1 Hz, H-6', Ar);
7.45 (s, 1H, H-2', Ar); 12.22 (br s, 1H, NH). 13C-NMR [(CD3)2SO] δ = 27.6 (NCH3); 102.10 (OCH2O);
109.10 (C-5); 109.81 (C-2); 113.70 (C=CH); 125.11 (C=CH); 126.90 (C-6); 126.91 (C-1); 148.40
(C-4); 149.02 (C-3); 164.61 (C=O); 179.0 (C=S). HRMS, m/z found: 262.0409 (calculated for
C12H10N2O3S, M+. requires: 262.0412).
(5Z)-5-(3,4-Dimethoxybenzylidene)-1-methyl-2-thioxoimidazolidin-4-one (4b): Method A: The product
4b was prepared from 1 (1.3 g, 10 mmol), propylamine (1.64 mL, 20 mmol, 2 equiv.) and 3,4-
dimethoxybenzaldehyde (2b, 1.670 g, 10 mmol) with a reaction time of 40 min. Yield= 96%.
Method B: The product 4b was prepared from 1 (1 g, 6.57 mmol) and N-[(3,4-dimethoxyphenyl)-
methylene]propan-1-amine (3b, 1.12 mL, 13.14 mmol, 2 equiv.) with a reaction time 60 min.
Yield = 92%.
1
Yellow needles, mp= 234-236 °C. H-NMR [(CD3)2SO] δ = 3.12 (s, 3H, NCH3); 3.92 (s, 3H,
OCH3); 3.93 (s, 3H, OCH3); 6.44 (d, 1H, J = 8.8 Hz, H-5', Ar); 6.81 (s, 1H, C=CH); 7.24 (d, 1H,
13
J = 6.4 Hz, H-6', Ar); 7.25 (s, 1H, H-2, Ar); 12.08 (br s, 1H, NH). C-NMR [(CD3)2SO] δ = 25.02
(NCH3); 55.51 (OCH3); 55.91 (OCH3); 113.82 (C-5); 114.53 (C-2); 116.20 (C=CH); 124.21 (C-6);
125.30 (C-1); 125.61 (C=CH); 148.30 (C-4); 149.11 (C-3); 166.32 (C=O); 178.80 (C=S). HRMS, m/z
found: 278.0701 (calculated for C13H14N2O3S, M+. requires: 278.0725).
(5Z)-5-(3,5-Dimethoxybenzylidene)-1-methyl-2-thioxoimidazolidin-4-one (4c): Method A: The product
4c was prepared from 1 (650 mg, 5 mmol), propylamine (1.32 mL, 10 mmol, 2 equiv.) and
3,5-dimethoxybenzaldehyde (2c, 1.240 g, 5 mmol) with a reaction of 40 min. Yield = 90%.

Molecules 2011, 16
7384
Method B: Compound 4c was prepared from 1 (1 g, 6.57 mmol.) and N-[(3,5-dimethoxyphenyl)-
methylene]propan-1-amine (3c, 1.12 mL, 13.14 mmol, 2 equiv.) with a reaction time 60 min.
Yield = 90%.
1
Yellow needles, mp > 260 °C. H-NMR [(CD3)2SO] δ = 3.24 (s, 3H, NCH3); 3.83 (s, 6H, OCH3);
13
6.49 (s, 1H, H-4', Ar); 6.85 (s, 1H, C=CH); 7.40 (s, 2H, H-2', H-6', Ar); 12.02 (br s, 1H, NH). C-
NMR [(CD3)2SO] δ = 25.21 (NCH3); 55.12 (OCH3); 103.04 (C-4); 109.31 (C-2); 123.52 (C=CH);
136.23 (C-1); 138.80 (C=CH); 160.62 (C-3); 167.31 (C=O); 178.84 (C=S). HRMS, m/z found:
278.0630 (calculated for C13H14N2O3S, M+. requires: 278.0725).
(5Z)-5-(3-Hydroxy-4-methoxybenzylidene)-1-methyl-2-thioxoimidazolidin-4-one (4d): The product 4d
was prepared from 1 (855 mg, 6.57 mmol), propylamine (1.08 mL, 13.14 mmol, 2 equiv.) and vanillin
(2d, 1 g, 6.57 mmol) with a reaction of 60 min. according to the standard procedure for method A.
Yield= 86%. Yellow needles, mp = 203-205 °C. 1H-NMR [(CD3)2CO] δ = 3.27 (s, 3H, NCH3); 3.95 (s,
3H, OCH3); 6.64 (s, 1H, C=CH); 6.92 (d, 1H, J = 8.7 Hz, H-5', Ar); 7.31 (d, 1H, J = 5.8 Hz, H-6', Ar);
13
7.32 (s, 1H, H-2', Ar); 8.25 (br s, 1H, OH); 10.84 (br s, 1H, NH). C-NMR [(CD3)2CO] δ = 26.70
(NCH3); 55.62 (OCH3); 113.33 (C-2); 113.51 (C=CH); 115.61 (C-5); 124.13 (C-6); 124.70 (C=CH);
124.84 (C-1); 147.82 (C-3); 148.53 (C-4); 16404 (C=O); 178.92 (C=S). 178.84 (C=S). HRMS, m/z
found: 264.0552 (calculated for C12H12N2O3S, M+. requires: 264.0569).
(5Z)-5-(2,3-Dihydro-1,4-benzodioxan-6-ylmethylene)-1-methyl-2-thioxoimidazolidin-4-one
(4e):
Method A: The product 4e was prepared from 1 (650 mg, 5 mmol), propylamine (0.8 mL, 10 mmol,
2 equiv.) and 1,4-benzodioxan-6-carboxaldehyde (2e, 1.540 g, 5 mmol) with a reaction of 60 min.
Yield= 98%.
Method B: The product 4e was prepared from 1 (1 g, 6.57 mmol) and N-[2,3-dihydro-1,4-benzo-
dioxan-6-yl)methylene]propan-1-amine (3e, 1.12 mL, 13.16 mmol, 2 equiv.) with a reaction time
60 min. Yield= 92%.
1
Yellow needles, mp > 260 °C. H-NMR [(CD3)2SO] δ = 3.83 (s, 3H, OCH3); 4.29 (t, 2H, J = 6.8
Hz, OCH2CH2O); 4.30 (t, 2H, J = 6.8 Hz, OCH2CH2O); 6.34 (s, 1H, C=CH); 6.78 (d, 1H, J = 8.1 Hz,
13
H-5', Ar); 7.06 (d, 1H, J = 8.3 Hz, H-6', Ar); 7.10 (s, 1H, H-2', Ar); 7.82 (br s, 1H, NH). C-NMR
[(CD3)2CO] δ = 56.20 (OCH3); 63.81 (OCH2CH2O); 64.44 (OCH2CH2O); 110.12 (C=CH); 113.61
(C-2); 116.23 (C-5); 124.04 (C-6); 124.62 (C-1); 126.04 (C=CH); 148.21 (C-3); 148.42 (C-4); 166.53
(C=O); 175,.90 (C=S). HRMS, m/z found: 276.0642 (calculated for C13H12N2O3S, M+. requires:
276.0569).
3.3. General Procedure for the Synthesis of Compounds 6 by S-Alkylation of 5-Arylmethylene-1-
methyl-2-thioxo imidazolin-4-ones 4(a-g) with Halogeno Compounds 5
In a 10 mL two-necked round-bottomed flask, equipped with a magnetic stirrer and reflux
condenser, a mixture of (5Z) 5-arylmethylene-1-methyl-2-thioxo-imidazolin-4-one 4 (10 mmoles),
halogeno compound R-X 5 (1-1.5 equiv.), potassium carbonate (0.618 g, 5 mmoles, 0.5 equiv.) and,
eventually potassium iodide KI (1.67 g, 10 mmoles) if X = Cl, Br for 5, in dry acetonitrile, was stirred
vigorously at the appropriate reaction temperature (60-81 °C) for 19-51 hours. After heating was
completed, the reaction mixture was allowed to cool down to room temperature; the solvent and the

Molecules 2011, 16
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volatile components were eliminated by rotary evaporation under reduced pressure. The crude residue
was dissolved in ethyl acetate (20 mL), the contents were filtered through a sintered glass disc; the
solution was recovered, and the solvent was removed under reduced pressure. The expected compound
6 was purified by recrystallization in EtOH. The precipitated product 6 was filtered off and further
dried under high vacuum (10−2 Torr) at 30 °C for 1 hour, which gave the desired (5Z)- 2-alkylthio-5-
arylmethylene-1-methyl-1,5-dihydro-imidazol-4-ones 6 as yellow solids. The pure compounds 6 were
characterized by 1H-, 13C-NMR and HRMS.
(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-2-ethylthio-1-methyl-1,5-dihydro-4H-imidazol-4-one
(6a):
The product 6a was prepared from (5Z)-5-(1,3-benzodioxol-5-ylmethylene)-1-methyl-2-thioxo-
imidazolidin-4-one (4a, 2.34 g, 13.2 mmol), ethyl iodide (5a, 1.45 mL, 15.9 mmol, 1.5 equiv.) and
potassium carbonate (816 mg, 6.61 mmol, 0.5 equiv.) in acetonitrile (40 mL) with a reaction time of 51
1
hours at 60 °C according to the general procedure. Yield= 60%. Yellow needles, mp > 260 °C. H-
NMR [(CD3)2SO] δ = 1.50 (t, 3H, J = 7.4 Hz, CH2CH3); 3.12 (s, 3H, NCH3); 3.33 (q, 2H, J = 7.4 Hz,
SCH2); 6.00 (s, 2H, OCH2O); 6.82 (d, 1H, J = 8.1 Hz, H-5', Ar); 6.84 (s, 1H, C=CH); 7.36 (dd, 1H,
13
J = 8.1, 1.0 Hz, H-6', Ar); 8.03 (s, 1H, H-2', Ar). C-NMR [(CD3)2CO] δ = 14.71 (CH2CH3); 25.63
(SCH2); 26.92 (NCH3); 101.82 (OCH2O); 108.84 (C-5'); 111.20 (C-2'); 124.04 (C=CH); 128.83 (C-6');
129.51 (C-1'); 137.52 (C=CH, C-5); 148.31 (C-4'); 149.50 (C-3'); 164.11 (C=N, C-2); 170,3 (C=O,
C-4). HRMS, m/z found: 290.0730 (calculated for C14H14N2O3S, M+. requires: 290.0725).
(5Z)-2-(Allylthio)-5-[(1,3-benzodioxol-5-yl)methylene)]-1-methyl-1,5-dihydro-4H-imidazol-4-one (6b):
The product 6b was prepared from 4a (500 mg, 1.91 mmol), potassium iodide (348 mg, 2.10 mmol,
1.1 equiv.), 3-bromopropene (5b, 348 mg, 0,25 mL, 2.10 mmol, 1.5 equiv.) and potassium carbonate
(132 mg, 0.95 mmol, 0.5 equiv.) in acetonitrile (6 mL) with a reaction time of 48 hours at 66 °C
1
according to the general procedure. Yield= 62%. Yellow needles, mp= 154-156 °C. H-NMR
[(CD3)2SO] δ = 3.17 (s, 3H, NCH3); 4.02 (d, 2H, J = 7.1 Hz, SCH2CH=CH2); 5.15 (d, 1H, J = 10.2 Hz,
SCH2CH=CH2); 5.40 (d, 1H, J = 17.2 Hz, SCH2CH=CH2); 6.00 (s, 2H, OCH2O); 6.10 (m, 1H,
SCH2CH=CH2); 6.82 (d, 1H, J = 8.1 Hz, H-5', Ar); 6,83 (s, 1H, C=CH-Ar); 7.37 (dd, 1H, J = 8.1,
1 Hz, H-6', Ar); 8.05 (s, 1H, H-2', Ar). 13C-NMR [(CD3)2CO] δ = 26.51 (NCH3); 33.32 (SCH2); 101.80
(OCH2O); 108.52 (C-5'); 110.81 (C-2'); 119.51 (CH=CH2); 124.10 (C=CH-Ar); 128.04 (C-6'); 129.03
(C-1'); 132.01 (CH=CH2); 136.91 (C=CH, C-5); 148.02 (C-4'); 149.21 (C-3'); 163.04 (C=N, C-2);
169.91 (C=O, C-4). HRMS, m/z found: 302.0723 (calculated for C15H14N2O3S, M+. requires:
302.0725).
(5Z)-5-[(1,3-Benzodioxol-5-yl)methylene]-1-methyl-2-propylthio-1,5-dihydro-4H-imidazol-4-one (6c) :
The product 6c was prepared from 4a (500 mg, 1.91 mmol), potassium iodide (348 mg, 2.10 mmol, 1.5
equiv.), 1-bromopropane (5c, 258 mg, 0,19 mL, 2.10 mmol, 1.5 equiv.) and potassium carbonate (132 mg,
0.95 mmol, 0.5 equiv.) in acetonitrile (6 mL) with a reaction time of 24 hours at 65 °C according to the
1
general procedure. Yield= 65%. Yellow needles, mp= 102-104 °C. H-NMR [(CD3)2SO] δ = 1.11
(t, 3H, J = 7.4 Hz, CH2CH3); 1.89 (sext, 2H, J = 7.3 Hz, CH2CH3); 3.14 (s, 3H, NCH3); 3.31 (t, 2H,
J = 7.2 Hz, SCH2); 6.04 (s, 2H, OCH2O); 6.82 (d, 1H, J = 8.1 Hz, H-5', Ar); 6.84 (s, 1H, C=CH); 7.36
(dd, 1H, J = 8.2, 1.4 Hz, H-6', Ar); 8.05 (d, 1H, J = 1.3 Hz, H-2', Ar). 13C-NMR [(CD3)2CO] δ = 13.51

Molecules 2011, 16
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(CH2CH3); 22.52 (CH2CH3); 26.50 (NCH3); 32.61 (SCH2); 101.41 (OCH2O); 108.40 (C-5'); 110.82
(C-2'); 123,.53 (C=CH); 128.04 (C-6'); 129.21 (C-1'); 137.12 (C=CH, C-5); 148.04 (C-4'); 149.03
(C-3'); 163.81 (C=N, C-2); 169.91 (C=O, C-4). HRMS, m/z found: 304.0861 (calculated for
C15H16N2O3S, M+. requires: 304.0882).
{[(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl]thio} aceto-
nitrile (6d): The product 6c was prepared from 4a (500 mg, 1.91 mmol), chloroacetonitrile (5d, 76 mg,
63 μL, 1.0 mmol, 1 equiv.) and potassium carbonate (168 mg, 1.0 mmol, 0.5 equiv.) in acetonitrile
(5 mL) with a reaction time of 19 hours at 81 °C according to the general procedure. Yield= 66%.
Yellow needles, mp = 211-213 °C. 1H-NMR [(CD3)2SO] δ = 3.09 (s, 3H, NCH3); 4,47 (s, 1H, SCH2);
6.11 (s, 2H, OCH2O); 6.95 (s, 1H, C=CH); 7.00 (d, 1H, J = 8.1 Hz, H-5', Ar); 7,64 (dd, 1H, J = 8.1,
13
1.1 Hz, H-6', Ar); 8.11 (d, 1H, J = 1.2 Hz, H-2', Ar). C-NMR [(CD3)2CO] δ = 16.41 (SCH2); 26.84
(NCH3); 102.14 (OCH2O); 109.03 (C-5); 110.81 (C-2); 117.34 (CN); 124.71 (C=CH); 128.70(C-1');
129.02 (C-6'); 136.51 (C=CH, C-5); 148.20 (C-4'); 149.71 (C-3'); 161.92 (C=N, C-2); 169.04 (C=O,
C-4). HRMS, m/z found: 301.0507 (calculated for C14H11N3O3S, M+. requires: 301.0521).
Ethyl {[(5Z)-5-(1,3-benzodioxol-5-ylmethylene)-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl]thio}-
acetate (6e): The product 6e was prepared from 4a (200 mg, 0.78 mmol), potassium iodide (193 mg,
1.16 mmol, 1.5 equiv.), ethyl bromoacetate (5e, 192 mg, 1.16 mmol, 1.1 equiv.) and potassium
carbonate (54 mg, 0.34 mmol, 0.5 equiv.) in acetonitrile (3 mL) with a reaction time of 14 hours at
1
60 °C according to the general procedure. Yield = 68%. Yellow needles, mp = 204-208 °C. H-NMR
[(CD3)2SO] δ = 3.14 (s, 3H, NCH3); 1.17 (t, 3H, J = 7.4 Hz, CH2CH3); 2.49 (q, 2H, J = 7.3 Hz,
CH2CH3); 4.36 (s, 2H, SCH2); 6.13 (s, 2H, OCH2O); 7,13 (d, 1H, J = 8.1 Hz, H-5', Ar); 7.21 (s, 1H,
J = 1.3 Hz, C=CH); 7.74 (s, 1H, H-2', Ar); 8.13 (dd, 1H, J = 8.1, 1.5 Hz, H-6', Ar). 13C-NMR
[(CD3)2CO] δ = 26.91 (NCH3); 14.22 (CH2CH3); 35.52 (CH2CH3); 62.11 (SCH2); 102.71 (OCH2O);
109.63 (C-5'); 109.81 (C-2'); 123.80 (C=CH); 127.43 (C-6'); 127.62 (C-1'); 136.44 (C=CH, C-5);
148.70 (C-4'); 150.43 (C-3'); 167.54 (C=N, C-2); 179.12 (C=O, C-4); 190.83 (C=O). HRMS, m/z
found: 348.0741 (calculated for C16H16N2O5S, M+. requires: 348.0780).
Ethyl {[(5Z)-5-(3,4-dimethoxybenzylidene)-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl]thio}acetate
(6f): The product 6f was prepared from (5Z)-5-(3,4-dimethoxybenzylidene)-1-methyl-2-
thioxoimidazolidin-4-one (4b, 201 mg, 0.71 mmol), potassium iodide (177 mg, 1.07 mmol, 1.5
equiv.), ethyl bromoacetate (5e, 178 mg, 1.07 mmol, 1.5 equiv.) and potassium carbonate (49 mg,
0.36 mmol, 0.5 equiv.) in acetonitrile (3 mL) with a reaction time of 19 hours at 60 °C according to the
general procedure. Yield= 62%. Yellow needles, mp = 252-254 °C. 1H-NMR [(CD3)2SO] δ = 3.14 (s,
3H, NCH3); 1.21 (t, 3H, J = 7.1 Hz, CH2CH3); 3.81 (s, 3H, OCH3); 3.82 (s, 3H, OCH3); 4.16 (q, 2H,
J = 7.3 Hz, CH2CH3); 4.35 (s, 2H, SCH2); 7.11 (d, 1H, J = 8.1 Hz, H-5', Ar); 7.18 (s, 1H, C=CH) ;
7,22 (s, 1H, H-2', Ar); 7.78 (dd, 1H, J = 8.1, 1.4 Hz, H-6', Ar). 13C-NMR [(CD3)2CO] δ = 14.22
(CH2CH3); 26.91 (NCH3); 35.92 (CH2CH3); 55.91 (OCH3); 56.11 (OCH3); 62.13 (SCH2); 112.52
(C-5'); 113.83 (C-2'); 123,.33 (C=CH); 125.12 (C-6'); 126.10 (C-1'); 136.73 (C=CH, C-5); 149.42
(C-4'); 151.93 (C-3'); 167.53 (C=N, C-2); 179.14 (C=O, C-4); 190.51 (C=O). HRMS, m/z found:
364.1086 (calculated for C17H20N2O5S, M+. requires: 364.1093).

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(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-2-[(3-hydroxypropyl)thio]-1-methyl-1,5-dihydro-4H-imidaz-ol-
4-one (6g): The product 6g was prepared from 4a (150 mg, 0.57 mmol), potassium iodide (141 mg,
0.85 mmol, 1.5 equiv.), 3-bromopropanol (5f, 118 mg, 0.85 mmol, 1.5 equiv.) and potassium
carbonate (39 mg, 0.28 mmol, 0.5 equiv.) in acetonitrile (4 mL) with a reaction time of 46 hours at
1
70 °C according to the general procedure. Yield= 42%. Yellow needles, mp= 256-258 °C. H-NMR
[(CD3)2SO] δ = 1.98 (q, 2H, J = 7,4 Hz, CH2CH2OH); 2.03 (t, 2H, J = 7.3 Hz, SCH2); 3.31 (t, 2H,
J = 7.2 Hz, CH2OH); 6.04 (s, 2H, OCH2O); 6.82 (d, 1H, J = 8,1 Hz, H-5', Ar); 6.84 (s, 1H, J = 1.3 Hz,
13
C=CH); 7.36 (s, 1H, H-2', Ar); 8.13 (d, 1H, J = 8,2 Hz; H-6', Ar). C-NMR [(CD3)2CO] δ = 27.41
(NCH3); 29.52 (CH2CH2CH2OH); 31.07 (SCH2); 59.11 (CH2OH); 101.42 (OCH2O); 108.13 (C-5');
109,8 (C-2); 118.73 (C=CH); 123.93 (C-6'); 126.83 (C-1'); 133.42 (C=CH, C-5); 148.72 (C-4'); 148.83
(C-3'); 168.52 (C=N, C-2); 177.91 (C=O, C-4).
4. Conclusions
In summary, new (5Z)-2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-ones
bearing two points of diversity have been developed according to a two step protocol. The first step
involves a solvent-free Knoevenagel condensation under microwave irradiation that produced (5Z)-5-
arylmethylene-2-thioimidazolidin-4-ones in good yields and high purity in a sterecontrolled fashion,
followed by a chemoselective S-alkylation with retention of double bond configuration. Although a
limited number of different and representative substituents on the 1-methyl-1,4-dihydro-4H-imidazol-
4-one core are represented here, it's obvious that a much larger diversity can be easily achieved.
Further studies are currently ongoing.
Acknowledgments
One of us (K.B.) thanks the "Ministère de l’Enseignement Supérieur et de la Recherche de la
République Algérienne Démocratique et Populaire" for a research fellowship. Financial support of this
program carried out under the French National Cancer Institute “Cancéropôle Grand Ouest” by
contracts PRIR 04-8390 and ACI 04-2254, is gratefully acknowledged. We also thank Merck Eurolab
Prolabo (France) for providing the Synthewave® 402 apparatus.
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).