Efficient combination of task-specific ionic liquid and microwave dielectric heating applied to one-pot three component synthesis of a small library of 4-thiazolidinones

Article abstract of DOI:10.1016/S0040-4020(03)00954-2

The first report of the use of task-specific ionic liquid as synthetic equivalent of ionic liquid-phase matrice for the preparation of a small library of 4-thiazolidinones is reported in this paper. The starting (ethyleneglycol)ionic liquid-phase is funct

Full text of DOI:10.1016/S0040-4020(03)00954-2

Tetrahedron 59 (2003) 6121–6130
Efficient combination of task-specific ionic liquid and microwave
dielectric heating applied to one-pot three component synthesis of
a small library of 4-thiazolidinones
*
Joan Fraga-Dubreuil and Jean Pierre Bazureau
Institut de Chimie, Synth e` se & Electrosynth e` se Organiques 3, Universit e´ de Rennes 1, UMR 6510, B aˆ t. 10A, Campus de Beaulieu, CS 74205,
F) 35042 Rennes Cedex, France
(
Received 7 April 2003; revised 23 May 2003; accepted 12 June 2003
Abstract—The first report of the use of task-specific ionic liquid as synthetic equivalent of ionic liquid-phase matrice for the preparation of a
small library of 4-thiazolidinones is reported in this paper. The starting (ethyleneglycol)ionic liquid-phase is functionalized in good yields
with 4-(formylphenoxy)butyric acid by using usual esterification reaction conditions (DCC/DMAP as catalyst). The synthesis of the ionic
liquid-phase bound 4-thiazolidinones was performed by a one-pot three-component condensation under microwave dielectric heating. The
final cleavage under microwave/catalysis strategy provides the expected 4-thiazolidinones in high purity after flash-chromatography
purification. According to the ionic liquid-phase organic synthesis (IoLiPOS) methodology, it was found that optimized reaction conditions
1
13
were performed by standard analytical methods (NMR, TLC). The H, C NMR spectrum of some representative 4-thiazolidinones and
ionic liquid-phase bound benzaldehyde are also reported.
q 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
Owing to their high polarity, the RTILs are also suitable for
8
microwave chemistry. Since the first report of microwave
9
1
The use of room temperature ionic liquids (RTILs) as
2
assisted synthesis in 1986, this technique has been accepted
as a method for reducing reaction time often by several
orders of magnitude and for increasing yields of product
molecular tools for green synthetic chemistry is a fast
growing area. The rising number of publications and
3
10
reviews is indicative of the potential of RTILs as ‘neoteric
solvents’ for a broad range of chemical and industrial
processes. RTILs made of organic cations such as
alkylpyridinium or dialkyl imidazolium and appropriate
anions have attracted much recent attention as solvents for
organic chemistry because they have melting points close or
near to room temperature. This is also due to a number of
6
intriguing physical and chemical properties of RTILs: they
compared to conventional methods. The combination of
modern microwave reactor technology and combinatorial
chemistry applications is a logical consequence of the
increased speed and effectiveness offered by microwave
4
1
1
dielectric heating. The dramatic rate enhancements in the
transformations can be mainly attributed to the high
temperatures that are rapidly reached by microwave
heating.
5
have high thermal and chemical stabilities, negligible vapor
pressure, non-flammability and high loading capacity. By a
judicious combination of cation and anion, physical proper-
ties have been accomplished by altering the length of alkyl
chain attached to the cation allowing for fine tuning
hydrophobicity, viscosity, polarity and molecular solvata-
tion. Ionic liquids are miscible with polar organic solvents
but non-miscible with water on one side and less-polar
organic solvents such as aliphatic or aromatic hydrocarbons,
diethylether, etc on the other. From this point of view ionic
Several reports have been published on the microwave
2
1
assisted multi-component synthesis libraries of medicinal
compounds using solid phase or soluble polymers such as
1
3
poly(ethyleneglycol) (PEG).
In connection with our research program on exploitation of
microwave-dielectric heating (mv) to room temperature
1
4
ionic liquid chemistry, we considered that hydrophilic
poly(ethyleneglycol)-ionic liquid matrices are potential
tools for synthetic applications in liquid-phase combinator-
7
liquids offer the potential of easy separation.
1
5
ial chemistry.
1
6
In a previous paper, we have found that a functionalized
PEG-ionic liquid phase (Fig. 1) can be used as a novel
matrix in liquid phase organic synthesis (LPOS) potentially
compatible with high-throughput production of combinatorial
Keywords: ionic liquid; microwave; 4-thiazolidinone; task-specific ionic
liquid; three-component condensation.
*
Corresponding author. Tel.: þ33-2-23-23-66-03; fax: þ33-2-23-23-63-
74; e-mail: jean-pierre.bazureau@univ-rennes1.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00954-2

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J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
Figure 1. Poly(ethyleneglycol)-ionic liquid matrices used for Ionic Liquid Phase Organic Synthesis (IoLiPOS).
libraries. In order to investigate the PEG-ionic liquid
matrices using solventless dielectric heating, we choose to
explore the 4-thiazolidinone moiety as a heterocyclic
scaffold. 4-Thiazolidinones have been reported to possess
formation on the [PEG mim][BF ] liquid phase 3 with
1 4
aromatic aldehydes (salicylaldehyde 4a and 4-hydroxyben-
zaldehyde 4b) bound to the ionic liquid moiety. For the
preparation of the starting 4-(formylphenoxy)butyric acid
6a,b, salicylaldehyde 4a and 4-hydroxybenzaldehyde 4b
were reacted in a Williamson ether synthesis with ethyl
bromobutyrate (EBB) to give esters 5a,b in quantitative
1
7
a wide range of biological activities (antifungal, anti-
1
histaminic or antimicrobial activity or use in the treatment
8
1
9
of inflammation, hypertension, renal failure, congestive
heart failure, uremia) and are most conveniently made by
the three-component condensation of a primary amine, an
aldehyde and either a mercaptoacetic acid (Fig. 2). Usually,
the reaction proceeds through the intermediate imine and
the stepwise assembly of 4-thiazolidinones has also been
2
7
28
yields (5a: 97%, 5b: 98%) followed by saponification
9
2
with KOH in refluxing MeOH (6a: 92%, 6b: 90%). The
aldehydes 6a,b could be assembled on the [PEG mim][BF ]
1
4
liquid phase 3. One of the most common transformations in
solid-phase organic synthesis (SPOS) or in liquid phase
organic synthesis (LPOS) involves the construction of an
ester linkage between a solid or liquid supported hydroxy or
halogen functionality and carboxylic acid derivative. The
activation of the carboxylic acid by carbodiimide still
constitutes the most frequently used method. As shown in
Scheme 1, the esterification of esters 6a,b (1.1 equiv.) with
2
0
reported. We wish to report now our efforts on the ionic
liquid phase organic synthesis (IoLiPOS) of 4-thiazolidi-
nones using microwave dielectric heating.
3
0
2
. Results and discussion
the ILP 3 in dry MeCN with dicyclohexyl carbodiimide
3
1
(DCC) and 5% of 4-dimethylamino pyridine (DMAP) as
catalyst produced the functionalized ionic liquid phases
3
2
For this study (Scheme 1), we have chosen to examine the
chemical and physical properties of the 1-(2-hydroxyethyl)-
7a,b in high yields (7a: 97%, 7b: 95%). During the work-up,
insoluble dicyclohexylurea (DCHU) was removed first by
filtration to ensure the final purity of the functionalized ionic
liquid phase, then the crude mobile pale yellow ILPs 7a,b
were washed successively twice with dry toluene (1:5 w/v),
AcOEt (1:5 w/v) and was further dried under high vacuum
3
-methylimidazolium tetrafluoroborate ([PEG mim][BF ])
1 4
3
in IoLiPOS methodology. This PEG -ionic liquid phase 3
1
2
1
(PEG-ILP) was prepared in two steps: the first step
involves an efficient solventless quaternization using a
2
2
monomode reactor with focused waves (Prolabo Synthe-
w
23
22
wave 402) and accurate control of power and tempera-
ture (by infrared detection) from an equimolar mixture of 2-
chloroethanol and methyl imidazole 1 (98% yield), then
followed by a facile anion metathesis with NH BF which
(10 Torr) at 608C for 1 h. The ILPs 7a,b were
characterized by mass spectrometry and proton NMR,
confirming that in esterification the major compound has a
molecular ion corresponding to the appropriate product.
4
4
produces the expected [PEG mim][BF ] liquid phase 3 in
1
4
8
5% yield. This PEG-ILP 3 present a low dynamic viscosity
85 cP at 258C) and provide a solution like environment for
In the second step, we initially examined the formation of
imines via condensation of amines 8 with the ILP 3 under
microwaves. Reactions were performed in open cylindrical
(
bound molecules, the BF4 coordinating ILP 3 would be
expected to be thermally stable to decomposition and
hence may prove more useful in microwave heating
experiments.
2
2
4
w
quartz reactor (B¼1 cm) with the Synthewave 402
microwave reactor. This reactor operates with an adjustable
power range 0–300 W and may be monitored either in
power or in temperature or both. An array of experiments
carried out with different reaction temperatures under
microwaves irradiations revealed that the optimal results
were obtained at 1008C after 20 min at 20% power (60 W)
level with continuous mixing (at elevated power levels, it is
possible to observe partial decomposition of the ILPs 9 by
microwave absorption, which results in lower yields). The
successful regioselective addition of amines 8 into the IL-
phase 3 will allow diversity introduction at this step.
There have been reports describing the solid phase synthesis
2
5
26
of 4-thiazolidinones and few reports where the nitrogen
of this heterocycle originates from an a-aminoacid with the
carboxylic function serving as the site of attachment to the
support. In our approach, we have examined the imine
Then we turned our attention to the scope and limitations of
4-thiazolidinone formation on the Il-phases 7a,b using a
one-pot three-component condensation for a rapid synthesis
of 4-thiazolidinones under microwaves. A stoichiometry of
1:1:1 of IL-phase 3: amine 8: mercaptoacetic acid 10,
Figure 2. Components for the synthesis of 4-thiazolidinones.

J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
6123
Scheme 1. Reagents and conditions: (i) chloroethanol (1 equiv.), mv, 1808C, Power¼20%, 10 min, N
1 equiv.), from 4a: K CO (2 equiv.), MeCN, reflux, 24 h, from 4b: K CO
HCl 5N, from 5b: reflux, 2 h, HCl 3N; (v) DCC (1 equiv.), DMAP (5%), dry MeCN, rt, 18 h; (vi) 8 (1 equiv.), 10 (1 equiv.), mv, 1008C, Power¼20%,
0–120 min; (vii) 8 (3 equiv.), mv, 1008C, 10 min; (viii) 8 (1 equiv.), t-BuOK (0.5 equiv.), mv, 1008C, 10–20 min; (ix) 8 or 12 (1 equiv.), t-BuOK
0.5 equiv.), mv, 1508C, 10 min.
2
; (ii) NH
4
BF
4
(3 equiv.), MeCN, 608C, 20 h; (iii) EBB
(
2
3
2
3
(1.5 equiv.), MeCN, reflux, 96 h,; (iv) KOH 2N, MeOH, from 5a: reflux, 1.5 h,
6
(
respectively, were found to react completely in the imine/
cyclization step at 1008C (Table 1). Progress of one-pot
cyclization was easily monitored by proton NMR spec-
troscopy and showed that optimized reaction conditions for
cyclization were achieved with a reaction time ranging from
not favored with the use of volatile amines 8 (i.e.
propylamine, isopropylamine, isobutylamine).
Cleavage of the ILP-bound thiazolidinones 11 was
performed by amide formation with primary amines 8 and
3
3
1
to 2 h under microwave exposure at 20% power level
60 W). Mercaptoacetic acid 10 was used to allow for the
secondary amines 12. Ester aminolysis, in general, occurs
under harsh conditions that require high temperatures and
extended reaction periods or the use of strong alkali metal
catalysts. A microwave-specific effect for the synthesis of
amides from non-enolizable esters and amines using t-
(
incorporation of a third diversity point.
We have found that condensation of a-mercapto carboxylic
acid 10 (1 equiv.) with ILPs-bound arylidene imines 9
provides 4-thiazolidinones 11 in yields ranging from 12 to
3
4
BuOK has been reported under microwave irradiation
3
5
using solventless conditions. With this information in
hand, we have conducted a series of experiments at various
temperatures using microwave dielectric heating. Our
straightforward procedure entails addition of a small
amount of solid potassium tert-butoxide (5%) to a premixed
mixture of ILP 11 and 1 equiv. of amine 8 or 12, and
exposing the reaction mixture to microwave irradiation for
the specified reaction time (10 or 20 min) at 1008C for
butylamine or at 1508C for b-substituted primary amines 8.
1
8
6% (estimated by H NMR spectroscopy in CDCl ). In our
3
approach, it was not necessary to use large excess of a-
mercapto carboxylic acid 10 with respect to imines 9 as
2
6b
described in the literature.
During the experiments, we
have observed that the best yields for products 11 were
obtained from a- and b-substituted primary amines 8 (i.e.
benzylamine, piperonylamine and 2,2-dimethoxyethyla-
mine), on the other hand the thiazolidinone formation is

6124
J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
Table 1. Results of the three component synthesis of 4-thiazolidinones 11a–l grafted on PEG -Ionic Liquid Phase from the [PEG
Phase 7a,b, amines 8 and a-mercapto carboxylic acid 10 by imine/cyclization under solventless microwave dielectric heating
1
1
mim][BF ] Ionic Liquid
4
1
R from 8
2
R from 10
a
b
Product 11
Reaction time
(
Conversion
(%)
min)
1
1
1
1
1
1
1
1
1
1
1
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
Bn
Bn
Bn
piperonyl
CH
CH
Pr
i-Pr
i-Bu
Bn
H
Me
90
90
90
120
120
120
80
86
79
60
71
84
82
41
12
42
61
71
47
CH
H
H
H
H
H
H
H
H
H
2
CO
2
H
2
CH(OMe)
-CHvCH
2
2
2
60
120
120
120
120
1j
1k
1l
Pr
i-Bu
a
w
Reactions were run in a focused microwave reactor (Synthewave 402, Merck Eurolab, Div. Prolabo, Fr) at 1008C, Power¼20% (60 W).
b
1
Conversion of 7a,b into 11 (ortho, para) estimated from the crude reaction mixture by H NMR (CDCl
3
, Bruker AC 300P, TMS as internal reference).
1
On completion of the reaction, as determined by H NMR, the
reaction mixture was extracted into chloroforme (1:5 w/v)
and subsequent product purification by flash chromato-
graphy on silica gel 60 F-254 (Merck) afforded the 4-
In our approach, we have found that it is possible to perform
perfect attachment of aromatic aldehydes to a TSIL-phase
via an esterification reaction using conventional protocol. 4-
Thiazolidinone formation is typically achieved in 1–2 h in
good yields by microwave irradiation with IL-phase bound
arylidene imine derivatives. The microwave heating can be
safely performed at atmospheric pressure and eliminates
the need for specialized pressure vessels for the one-pot
three component condensations of a-mercapto
carboxylic acids, amines and aldehydes to generate the
4-thiazolidinone moiety on the IL-phase. Cleavage of
the IL-phase bound thiazolidinone was realized with
various amines and t-BuOK as catalyst under microwave
heating and allowed for the incorporation of a fourth
diversity point. The presented examples indicate that the
microwave/catalysis strategy provides a wide scope in the
development of pure amides with moderate elevated
temperature (1508C) but without large molar excess of
reagent.
thiazolidinones 13 or 14 using CHCl or AcOEt as eluent.
3
The purified products were characterized by conventional
techniques ( H, C NMR and HRMS). The overall yields of
isolated 4-thiazolidinones 13 and 14 (Table 2) are quite
respectable in their own right, but the main advantage of
having assembled the molecules on the ionic liquid phase
1
13
[
PEG mim][BF ] 3 is demonstrated by the purities of the
1 4
crude material: no further purification is needed. Table 2
outlines 12 representatives examples where initial imine/
cyclization step were proceeded efficiently.
3. Conclusion
In conclusion, we have demonstrated that the combination
of task-specific ionic liquid (TSIL) and microwave
dielectric heating allow a rapid and practical preparation
of a small library of amido 4-thiazolidinones. To our
knowledge, this methodology has never been reported and
may complement those existing in the literature.
The specific advantages offered by the use of TSILs as new
tools in liquid-phase organic synthesis (LPOS) are the
following: (1) the routine product isolation is very simple
because the side product is removed by washings from the
IL-phase with the appropriate solvent/eluent, (2) the cleaved

J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
6125
Table 2. Representative 4-thiazolidinones 13 or 14 and results obtained for conversion of 11 grafted on PEG
primary amine 8 or secondary amine 12 using solventless microwave dielectric heating (in the Synthewave 402 reactor)
1
-Ionic Liquid Phase into 13 or 14 by addition of
1
R from 8
2
R from 10
a
Yield (%)
Product 13 or 14
Reaction conditions for cleavage
b
c
Time (min)
Amine 8 or 12
Method
1
1
1
1
1
1
1
1
1
1
1
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
Bn
Bn
Bn
Bn
Bn
H
H
H
Me
CH
H
H
H
H
-
Pr-NH
Bu-NH
Piperonyl-NH
2
vii
viii
ix
vii
vii
vii
ix
vii
ix
ix
20
10
10
20
20
20
10
10
30
10
10
10
44
47
40
61
41
40
39
47
30
26
30
25
2
2
Pr-NH
Pr-NH
Pr-NH
2
2
2
2 2
-CO H
Piperonyl
Piperonyl
Bn-NH
2
Pr-NH
CH
CH
Bn
Bn
Bn
2
-CH(OMe)
-CHvCH
2
2
2
2
Bn-NH
2
4a
4b
4c
Piperidine
Pyrrolidine
Morpholine
-
-
ix
ix
a
Overall yield of isolated product obtained after purification by flash chromatography on silica gel 60 F-254 (Merck).
Reaction conditions used under microwave irradiation: (vii) 8 (3 equiv.), 1008C; (viii) 8 (1 equiv.), t-BuOK (0.5 equiv.), 1008C; (ix) 8 or 12 (1 equiv.),
b
t-BuOK (0.5 equiv.), 1508C.
Reaction time estimated by conversion of 9 into 13 or 14 in the crude reaction mixture by H NMR (CDCl
c
1
3
, Bruker AC 300P, TMS as internal reference).
product was obtained with high purity after flash chroma-
tography, (3) at each step of the synthesis, the ILPs bound
products allow standard analytical methods ( H NMR,
TLC) to be used to monitor reaction progress, (4) the high
polarity of IL-phases is suitable for microwave dielectric
heating, and the combination of ILP/microwave decreases
the viscosity of the reaction medium and gives significant
rate enhancements, and (5) the IL-phases are easy to prepare
by a judicious combination of cation and anion.
the following order: d value, multiplicity (s, singulet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad),
number of protons, coupling constants J are given in Hertz.
The mass spectra (HRMS) were taken on a VARIAN MAT
311 at an ionizing potential of 70 eV in the Centre R e´ gional
de Mesures Physiques de l’Ouest (CRMPO, Rennes). For
the dynamic viscosity, the measurements were carried out at
258C on the AR 1000 microviscosimeter (TA Instruments)
with a stainless cone plate geometry (diameter: 40 mm,
1
0
angle: 181 ). A flow procedure was applied from 0.06 to
2
1
We are currently exploring the scope and potential of
microwave dielectric heating assisted ionic liquid phase
organic synthesis (IoLiPOS) by extending the methodology
200 s in 3 min with 20 points by decade. Acetonitrile was
distilled over calcium chloride after standing overnight and
˚
stored over molecular sieves (3 A). Solvents were evapor-
3
6
described herein to other heterocyclic targets, and the
simplicity of the experimental procedures renders this
approach particularly attractive.
ated with a BUCHI rotary evaporator. All reagents were
purchased from Acros, Aldrich Chimie, Fluka France and
used without further purification. 1-Methylimidazole 1 was
distilled from CaH prior to use.
2
4
. Experimental
4.1.1. 1-(2-Hydroxy-ethyl)-3-methylimidazolium chlor-
ide (2). A mixture of freshly distilled 1-methylimidazole 1
(15 g, 182.6 mmol) and 2-chloroethanol (14.70 g,
4
.1. General
182.6 mmol) was placed in a cylindrical quartz reactor
Melting points were determined on a Kofler melting point
apparatus and are uncorrected. Thin-layer chromatography
(B¼4 cm). The reactor was then introduced into a
Synthewavew 402 Prolabo microwave reactor [2.45 GHz,
adjusted power within the range 0–300 W and a wave guide
(single mode T01) fitted with a stirring device and an IR
temperature detector]. The stirred liquid mixture was
irradiated twice at 20% power level for 5 min at 1808C.
Then the mixture was allowed to cool down and a white
solid formed rapidly (,5 min) at 258C. The crude solid that
had formed was filtered off (under nitrogen), washed
successively with anhydrous ether (3£30 mL), dry aceto-
nitrile (2£20 mL), and vacuum dried in a dessicator over
(
TLC) was accomplished on 0.2 mm precoated plates of
silica gel 60 F-254 (Merck). Visualization was made with
ultraviolet light (254 and 365 nm) or with a fluorescence
indicator. For preparative column chromatography, silica
1
gel 60 F-254 Merck (230–240 mesh ASTM) was used. H
NMR spectra were recorded on BRUKER ARX 200 P
(200 MHz), BRUKER AC 300 P (300 MHz) spectrometers,
13
C NMR spectra on BRUKER ARX 200 P (50 MHz),
BRUKER AC 300 P (75 MHz) spectrometers. Chemical
shifts are expressed in parts per million downfield from
tetramethylsilane as an internal standard. Data are given in
CaCl for 1 h. The solid salt [PEG mim][Cl] 2 was further
2 1
2
2
dried under high vacuum (10 Torr) at 608C for 8 h and

6126
J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
was stored (23.44 g, 94% yield) in the dark at 48C under
nitrogen. Recrystallization from dry MeCN gave 2 in 80%
assium carbonate (11.31 g, 58.89 mmol) and ethyl bromo-
butyrate (7.62 g, 39.06 mmol) in refluxed acetonitrile
(80 mL) with a reaction time of 4 days. Then, acid 4-(4-
formyl-phenoxy)-butyric 6b was synthetized according to
the method described for 6a which gave the expected acid
1
yield as colourless needles, mp¼86–888C. H NMR (D O,
2
200 MHz) d 3.82 (s, 3H); 3.84 (t, 2H, J¼5.9 Hz); 4.23 (t,
2H, J¼5.9 Hz); 7.37 (t, 1H, J¼1.2 Hz, H-4, H-5); 7.41 (t,
1H, J¼1.2 Hz, H-4, H-5); 8.67 (s, 1H, H-2).
1
6b in 97% yield as colourless needles, mp¼245–2468C. H
6
NMR (DMSO d , 200 MHz) d 1.96 (quint, 2H, J¼6.9 Hz);
4
.1.2. 1-(2-Hydroxy-ethyl)-3-methylimidazolium tetra-
fluoroborate [PEG mim][BF ] (3). A mixture of 1-(2-
2.39 (t, 2H, J¼7.3 Hz); 4.08 (t, 2H, J¼6.6 Hz); 7.08–7.83
(d, 2H, J¼8.7 Hz, Ar); 9.84 (s, 1H, CHO).
1
4
Hydroxy-ethyl)-3-methylimidazolium chloride 2 (10 g,
1.54 mmol) and NH BF (6.46 g, 61.54 mmol, 1 equiv.)
in dry acetonitrile (160 mL) was stirred vigorously at 258C
6
4.1.5. 1-{2-[4-(2-Formyl-phenoxy)-butyryloxy]-ethyl}-3-
methyl-imidazolium tetrafluoroborate (7a). To a mixture
of dicyclohexylcarbodiimide (2.97 g, 14.42 mmol) and
dimethylaminopyridine 5% (88 mg, 0.7 mmol) in dry
acetonitrile (75 mL) were added successively the ionic
liquid phase [PEG mim][BF ] 3 (3.08 g, 14.42 mmol) in
4
4
under nitrogen for 24 h. After elimination of the precipitated
salt (NH Cl) on a filter paper, the resulting filtrate was
4
quickly refiltered through a short column of Celitew to
remove some residual salt and finally concentrated by rotary
evaporation that gave the expected mobile liquid phase 3 in
1
4
one portion, then 4-(2-formylphenoxy)butyric acid 6a (3 g,
14.42 mmol). After vigorous stirring at room temperature
9
dried under high vacuum (10 Torr) at 608C for 6 h. It is
8% yield (12.91 g). The ionic liquid phase 3 was further
2
2
0
for 18 h, the insoluble N,N -dicyclohexylurea was removed
recommandle to handle the [PEG mim][BF ] ionic liquid
4
by filtration. The filtrate was concentrated under reduced
pressure and the resulting crude reaction mixture was
washed three times with toluene (20 mL). Removal of the
solvent in vacuo lead to a pale yellow viscous oil in 97%
yield. The ionic liquid phase 7a was stored under inert
1
phase 3 in the dark under an inert atmosphere at 48C.
2
1
21
1
Dynamic viscosity: 86 cP at 258C (0.01 g cm
s
). H
NMR ((CD ) CO, 300 MHz) d 3.92 (t, 2H, J¼4.8 Hz); 4.01
3
2
(
1
8
s, 3H); 4.22 (br. s, 1H, OH); 4.38 (t, 2H, J¼5 Hz); 7.63 (t,
1
H, J¼1.6 Hz, H-4, H-5); 7.68 (t, 1H, J¼1.6 Hz, H-4, H-5);
atmosphere at 48C. H NMR ((CD ) CO, 300 MHz) d 2.15
3
2
.85 (s, 1H, H-2).
(quint., 2H); 2.66 (t, 2H); 4.02 (s, 1H); 4.20 (t, 2H); 4.52 (t,
H); 4.66 (t, 2H); 7.06 (t, 1H); 7.20 (d, 1H); 7.63 (ddd, 1H);
7.67 (t, 1H); 7.73 (dd, 1H); 7.78 (t, 1H); 9.02 (s, 1H); 10.44
2
4.1.3. Acid 4-(2-formyl-phenoxy)-butyric (6a). To a
stirred suspension of 2-hydroxybenzaldehyde 4a (5 g,
1
3
(s, 1H). C NMR ((CD ) CO, 75 MHz) d 24.98 (thept,
3 2
4
5
0.94 mmol) and potassium carbonate (11.31 g,
8.89 mmol) in acetonitrile (80 mL) was added dropwise
J¼129, 2.5 Hz); 30.82 (tt, J¼129, 4.5 Hz); 36.60 (q,
J¼144 Hz); 49.49 (t, J¼145 Hz); 63.12 (tt, J¼151,
3.2 Hz); 68.32 (tquint, J¼146, 4.3 Hz, OCH2); 114.02
(ddt, J¼161, 7.6, 1.5 Hz, C-3); 121.46 (dd, J¼164, 7.8 Hz,
over 15 min at room temperature ethyl bromobutyrate
7.62 g, 39.06 mmol), then the mixture was heated for
0 h. The reaction mixture was allowed to cool down to
(
2
0
0
C-5); 123.86 (dm, J¼204 Hz, C-4 , C-5 ); 124.70 (dm,
0 0
room temperature. After filtration and removal solvent in
vacuo, diethyl ether (50 mL) was added to the crude
reaction mixture and the resulting solution was filtered
J¼204 Hz, C-4 , C-5 ); 125.65 (dm, J¼34 Hz, C-1); 128.43
(ddt, J¼161, 8.5, 1.9 Hz, C-6); 137.03 (ddd, J¼160, 9.1,
0
1.9 Hz, C-4); 138.05 (dm, J¼222 Hz, C-2 ); 163.10 (m, C-
w
though a pad of Celite to remove the precipitated salt KBr,
2); 173.15 (m, CO); 189.76 (ddd, J¼180, 4.2, 1.6 Hz,
and the solvent was removed on a Rotovapor. The crude
reaction mixture gave the expected ethyl 4-(2-formyl-
phenoxy)-butyrate 5a as a mobile and colourless oil in
CHO); HRMS, m/z: 317.1497 found (calcd for C H N O ,
1
7 21 2 4
þ
M requires: 317.1501).
9
7% yield.
4.1.6. 1-{2-[4-(4-Formyl-phenoxy)-butyryloxy]-ethyl}-3-
methyl-imidazolium tetrafluoroborate (7b). To a mixture
of dicyclohexylcarbodiimide (2.97 g, 14.42 mmol) and
dimethylaminopyridine 5% (88 mg, 0.7 mmol) in dry
acetone (75 mL) were added successively the ionic liquid
phase [PEG mim][BF ] 3 (3.08 g, 14.42 mmol) in one
To a solution of ethyl 4-(2-formyl-phenoxy)-butyrate 5a
5 g, 21.16 mmol) in methanol (25 mL) was added dropwise
(
a solution of potassium hydroxyde 2N (2.85 g, 50.79 mmol)
over 20 min under vigorous magnetic stirring. The reaction
mixture was refluxed during 2 h. After elimination of
solvent in a rotary evaporator, the precipitated acid 6a was
obtained at pH 1 by addition of a solution of HCl 3N in the
crude residue. The precipitated crude acid 6a was filtered
off, washed with deionized water (3£50 mL) and dried
under reduced pressure during 3 h. The expected acid 6a
1
4
portion, then 4-(4-formylphenoxy)butyric acid 6b (3 g,
14.42 mmol). After vigorous stirring at room temperature
0
for 18 h, the insoluble N,N -dicyclohexylurea was removed
by filtration. The filtrate was concentrated under reduced
pressure and the resulting crude reaction mixture was
washed three times with AcOEt (20 mL). Removal of the
solvent in vacuo lead to a pale yellow viscous oil in 95%
yield. The ionic liquid phase 7b was stored under an inert
was obtained in 93% yield as colourless needles, mp¼91–
1
9
28C. H NMR (CDCl , 200 MHz) d 2.25 (quint, 2H,
3
1
J¼6.8 Hz); 2.65 (t, 2H, J¼7 Hz); 4.19 (t, 2H, J¼6 Hz); 7.02
atmosphere at 48C. H NMR ((CD ) CO, 300 MHz) d 2.10
3
2
(
m, 2H, H-3, H-5); 7.57 (ddd, 1H, J¼8.2, 1.8 Hz, H-4); 7.85
dd, 1H, J¼7.7, 1.7 Hz, H-6); 10.50 (s, 1H, CHO); 10.81 (br.
(quint, 2H, J¼6.61 Hz); 2.93 (t, 2H, J¼7.3 Hz); 4.02 (s,
3H); 4.15 (t, 2H, J¼6.30 Hz); 4.55 (t, 2H, J¼5.3 Hz); 4.66
(t, 2H, J¼5.3 Hz); 7.10 (d, 1H, J¼8.7 Hz, H-3, H-5); 7.66 (t,
(
s, 1H, OH).
0
0
0
1
H, J¼1.6 Hz, H-4 , H-5 ); 7.77 (t, 1H, J¼1.6 Hz, H-4 , H-
0
0
4
.1.4. Acid 4-(4-formyl-phenoxy)-butyric (6b). Ethyl 4-
4-formyl-phenoxy)-butyrate 5b was prepared in 98% yield
from 4-hydroxybenzaldehyde 4b (5 g, 40.94 mmol), pot-
5 ); 7.89 (t, 1H, J¼8.8 Hz, H-2, H-6); 9.00 (s, 1H, H-2 );
9.91 (s, 1H, CHO). C NMR ((CD ) CO, 75 MHz) d 24.85
3 2
1
3
(
(tm, J¼130 Hz); 30.67 (tt, J¼129, 4.4 Hz); 36.48 (q,

J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
6127
J¼144 Hz); 49.39 (t, J¼146 Hz); 63.09 (t, J¼151 Hz);
7.89 (tquint, J¼145, 4.6 Hz); 115.59 (dd, J¼163, 4.5 Hz,
128.74 (dd, J¼161, 6.6 Hz, C-2, C-6); 128.84 (dm,
0
(m, C-1 ); 159.53 (m, C-4); 171.12 (m, C-4, CO); 172.58 (m,
0
6
J¼160 Hz, C-3 , C-5 ); 130.50 (t, J¼7.5 Hz, C-1); 135.28
0
0
0
CONH); HRMS, m/z: 413.1901 found (calcd for
C-3, C-5); 123.70 (dm, J¼204 Hz, C-4 , C-5 ); 124.56 (dm,
0
0
J¼204 Hz, C-4 , C-5 ); 130.80 (dt, J¼23.8, 6.9 Hz, C-4);
þ
1
32.58 (ddd, J¼161, 7.2, 2 Hz, C-2, C-6); 137.81 (dm,
C H N O S, [MþH] requires: 413.1899).
2
3 29 2 3
0
J¼222 Hz, C-2 ); 164.60 (tt, J¼9.3, 2 Hz, C-1); 173.24 (m,
CO);181.84(dt,J¼174,4.6 Hz,CHO);HRMS, m/z: 317.1499
4.2.2. 4-[4-(3-Benzyl-4-oxo-thiazolidin-2-yl)-phenoxy]-
1
þ
found (calcd for C H N O , M requires: 317.1501).
7 21 2 4
N-butyl-butyramide (13b). Yield¼47%.
H
NMR
1
(
CDCl , 300 MHz) d 0.90 (t, 3H, J¼7.2 Hz); 1.31 (sext, 2H,
3
4
.2. Standard procedure for the three-component
J¼6.2 Hz); 1.45 (quint, 2H, J¼6.5 Hz); 2.15 (quint, 2H,
J¼6.2 Hz);2.37(t, 2H, J¼7.3 Hz); 3.27(q, 2H, J¼7 Hz); 3.51
synthesis of 4-thiazolidinone 13 or 14 from the ionic
liquid phase 7 under solventless microwave dielectric
heating
(d, 1H, J¼14.7 Hz); 3.80 (dd, 2H, J¼37.47, 15.58 Hz, SCH );
2
4.01 (t, 2H, J¼6 Hz); 5.11 (d, 1H, J¼14.7 Hz); 5.35 (s, 1H,
1
3
CH); 5.73 (t large, 1H, NH); 6.83–7.32 (m, 9H, Ar). C NMR
In a cylindrical quartz reactor (B¼1.8 cm) were placed an
equimolar mixture of 1-{2-[4-(formyl-phenoxy)-butyry-
loxy]-ethyl}-3-methyl-3H-imidazol-1-ium tetrafluoroborate
(CDCl , 75 MHz) d 13.79 (qt, J¼125, 2.5 Hz); 20.08 (tm,
3
J¼126 Hz); 25.20 (tm, J¼122 Hz); 31.70 (tm, J¼125 Hz);
32.08 (tm, J¼122 Hz); 33.12 (t, J¼145 Hz); 39.30 (tm,
J¼137 Hz); 46.06 (tm, J¼141 Hz); 62.49 (d, J¼157 Hz);
67.03 (t, J¼145 Hz); 114.91 (d, J¼160 Hz, C-3, C-5); 127.79,
7
b (0.5 g, 1.5 mmol), freshly distilled or dry amine 8
1.5 mmol) and commercial a-mercapto carboxylic acid 10
(
(
0 0 0
128.39, 128.72, 128.75, 130.73 (m, C-2, C-6, C-2 , C-3 , C-4 ,
1.5 mmol). The reactor was then introduced into a
w
0
(m); 172.19 (m, CONH); HRMS, m/z: 427.2046 found (calcd
0
0
Synthewave 402 Prolabo microwave reactor. The stirred
liquid mixture was irradiated at 1008C (20% power level)
for a reaction time ranging from 60 to 120 min (see Table 1).
After microwave dielectric heating, the crude reaction
mixture was allowed to cool down at room temperature and
C-5 , C-6 , C-1); 138.29 (m, C-1 ); 159.55 (m, C-4); 171.11
þ
for C H N O S, [MþH] requires: 427.2055).
2
4 31 2 3
4.2.3. N-Benzo[1,3]dioxol-5-yl-methyl-4-[4-(3-benzyl-4-
oxo-thiazolidin-2-yl)-phenoy)-butyramide (13c). Yield¼
1
was controlled by H NMR spectroscopy in CDCl3 or
1
eventually by TLC analysis with 0.2 mm precoated plates of
silica gel 60F-254 (Merck), visualization was made with
ultraviolet light (254 or 365 nm). The ester aminolysis of the
crude product 11 was realized with vigorous stirring under
nitrogen using the appropriate method (see Table 2): (vii)
addition of dry amine 8 (4.5 mmol) followed by microwave
irradiation at 1008C for 10–20 min or, (viii) addition of
amine 8 (1.5 mmol) and potassium terbutoxide (0.75 mmol,
40%. H NMR (CDCl , 300 MHz) d 2.12 (quint., 2H,
3
J¼6.3 Hz); 2.41 (t, 2H, J¼7 Hz); 3.50 (d, 1H, J¼14.70);
3.75 (dd, 2H, J¼38, 15.6 Hz, SCH ); 3.98 (t, 2H, J¼6 Hz);
2
5.07 (d, 1H, J¼14.7 Hz); 5.34 (s, 1H); 5.86 (s, 2H); 6.68–
1
3
7.30 (m, 1H, NHþAr). C NMR (CDCl , 75 MHz) d 25.16
3
(tm, J¼130 Hz); 32.72 (tm, J¼130 Hz); 33.09 (t,
J¼146 Hz); 43.34 (tm, J¼137 Hz); 46.04 (tm, J¼137 Hz);
62.52 (d, J¼144 Hz); 67.09 (t, J¼140 Hz); 101.06 (t,
0
0
8
4 mg, 0.5 equiv.). The stirred mixture was heated at 1008C
J¼174 Hz); 108.24 (d, J¼164 Hz, C-2 ); 108.45 (dm,
00
for 10 min or, (ix) addition of dry amine 8 or 12 (1.5 mmol)
and t-BuOK (0.5 equiv.) followed by heating at 1508C with
vigorous stirring for 10 min. After ester aminolysis, the
reaction mixture was allowed to cool down at 258C and
chloroform (4 mL) was added in the reactor. Then, the
solution was half concentrated by rotary evaporation and the
crude solution was purified by flash chromatography
J¼162 Hz, C-6 ); 114.90 (d, J¼159 Hz, C-3, C-5); 120.99
(dq, J¼161, 6.53 Hz, C-2, C-6); 127.73, 127.93, 128.36,
0
0
0
0
0
128.66, 128.74, 128.78 (m, C-2 , C-3 , C-4 , C-5 , C-6 , C-
0
C-1 ); 146.86 (m, C-3 ); 147.84 (m, C-4 ); 159.50 (C-4);
0
0
5 ); 130.64 (t, J¼7.6 Hz, C-1); 132.39 (m, C-1 ); 135.32 (m,
0
171.17 (m, C-4, CO); 172.39 (m, CONH); HRMS, m/z:
0
00
00
þ
505.1802 found (calcd for C H N O S, [MþH] requires:
2
8 29 2 5
(
(
column: B¼1 cm, H¼7 cm) on silica gel 60F-254
505.1797).
Merck) with CHCl3 or AcOEt as eluent. The desired
fraction was concentrated in vacuo and gave compound 13
or 14 as a nearly yellowish pure oil. The pure products 13a–
i and 14a–c were characterized by H, C NMR and
HRMS.
4.2.4. 4-[4-(3-Benzyl-5-methyl-4-oxo-thiazolidin-2-yl)-
1
phenoxy]-N-propyl-butyramide (13d). Yield¼61%.
H
1
13
NMR (CDCl , 300 MHz) d 0.89 (t, 3H, J¼7.4 Hz); 1.50
3
(sext., 2H, J¼7.3 Hz); 1.61–1.67 (d, 3H, J¼7 Hz); 2.12
(
quint., 2H, J¼6.4 Hz); 2.39 (t, 2H, J¼7.1 Hz); 3.20 (q, 2H,
4
.2.1. 4-[4-(3-Benzyl-4-oxo-thiazolidin-2-yl)-phenoxy]-
1
J¼6.7 Hz); 3.50–3.53 (d, 1H, J¼14.8 Hz); 3.99 (t, 2H,
J¼7 Hz); 3.99–4.11 (qd, J¼7.1, 1.05 Hz); 5.07–5.12 (d,
1H, J¼12.9 Hz); 5.29 (d, 1H, J¼1.7 Hz); 5.31 (s, 1H); 6.00
N-propyl-butyramide (13a). Yield¼46%.
H NMR
CDCl , 300 MHz) d 0.89 (t, 3H, J¼7.2 Hz); 1.50 (sext.,
(
2
3
1
3
H, J¼7.20 Hz); 2.09 (quint., 2H, J¼7.6 Hz); 2.39 (t, 2H,
(br t, 1H, J¼5.2 Hz, NH); 6.87–7.27 (m, 9H, Ar). C NMR
J¼7.2 Hz); 3.17 (q, 2H, J¼6.6 Hz); 3.52 (d, 1H,
(CDCl , 75 MHz) d 11.38 (qt, J¼126, 4.2 Hz); 20.26 (q,
3
J¼14.7 Hz); 3.77 (dd, 2H, J¼39.3, 15.6 Hz, SCH ); 3.99
J¼131 Hz); 22.86 (tm, J¼131 Hz); 25.22 (tm, J¼125 Hz);
32.84 (tm, J¼125 Hz); 41.26 (tm, J¼137 Hz); 42.39 (dq,
J¼142, 4.7 Hz); 46.31 (tm, J¼141 Hz); 60.84 (dm,
J¼157 Hz); 67.12 (t, J¼145 Hz); 114.91 (dd, J¼156,
5.5 Hz, C-3, C-5); 127.87, 127.96, 128.52, 129.24, 130.07
2
(
6
t, 2H, J¼6.30 Hz); 5.05 (d, 1H, J¼14.7 Hz); 5.35 (s, 1H);
1
3
.50 (br t, 1H, J¼5.2 Hz, NH); 6.86–7.27 (m, 9H, Ar).
C
NMR (CDCl , 75 MHz) d 11.44 (qt, J¼126, 4.03 Hz); 21.75
3
(
tm,J¼126 Hz); 25.25 (tm, J¼125 Hz); 32.70 (tm,
0
0
0
0
0
J¼125 Hz); 33.06 (t, J¼146 Hz); 41.23 (tm, J¼140 Hz);
6.01 (tm, J¼140 Hz); 62.52 (d, J¼153 Hz); 67.17 (t,
J¼142 Hz); 114.89 (d, J¼159 Hz, C-3, C-5); 127.88 (dt,
(m, C-2, C-6, C-2 , C-3 , C-4 , C-5 , C-6 , C-1); 135.49 (m,
0
HRMS, m/z: 427.2052 found (calcd for C H N O S,
4
C-1 ); 159.55 (m, C-4); 172.31 (m, C-4, CO); 173.90 (CO);
2
4 31 2 3
0
0
0
þ
J¼168, 7.4 Hz, C-4 ); 128.25 (dm, J¼159 Hz, C-2 , C-5 );
[MþH] requires: 427.2055).

6128
J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
1
4
.2.5. Acide [3-benzyl-4-oxo-2-[4-(3-propylcarbamoyl-
H NMR (CDCl , 300 MHz) d 0.90 (t, 3H, J¼7.4 Hz);
3
propoxy)-phenyl]-thiazolidin-5-yl]-acetique (13e). Yield¼
1.50 (sext, 2H, J¼7.3 Hz); 2.11 (quint, 2H, J¼6.5 Hz); 2.38
1
4
1
2
1
1%. H NMR (CDCl , 300 MHz) d 0.88 (t, 3H, J¼7.4 Hz);
(t, 2H, J¼7.3 Hz); 2.68 (dd, 1H, J¼14.2, 6.8 Hz); 3.20 (q,
2H, J¼6.3 Hz); 3.31 (s, 3H); 3.36 (s, 3H); 3.74 (dd, 2H,
3
.48 (sext., 2H, J¼7.2 Hz); 2.08 (quint.; 2H, J¼5.7 Hz);
.37 (t, 2H, J¼7 Hz); 2.75 (m, 2H); 3.17 (m, 2H); 3.48 (d,
H, J¼14.7 Hz); 3.97 (t, 2H, J¼6.9 Hz); 4.29 (dd, 1H,
J¼21.8, 15.3 Hz, SCH ); 4.01 (t, 2H, J¼6 Hz); 4.49 (m,
2
2H); 5.79 (s, 1H); 6.27(br. t, 1H, NH); 6.87 (d, 1H,
J¼8.7 Hz, Ar); 7.21 (d, 1H, J¼8.7 Hz, Ar). C NMR
1
3
J¼9.1, 4.2 Hz); 5.03 (d, 1H, J¼14.5 Hz); 5.25 (d, 1H,
J¼1.5 Hz); 5.27 (s, 1H,); 5.97–6.03 (br t, 1H, NH); 6.80–
(CDCl , 75 MHz) d 11.38 (qt, J¼125, 4.2 Hz); 22.78 (tm,
3
1
3
7
.25 (m, 9H, Ar). C NMR (CDCl , 75 MHz) d 11.40 (qt,
3
J¼125 Hz); 25.17 (tm, J¼127 Hz); 32.68 (tm, J¼125 Hz);
J¼126, 4.03 Hz); 22.82 (tm, J¼130 Hz); 25.23 (tm,
32.72 (t, J¼145 Hz, CH S); 41.18 (tm, J¼132 Hz); 43.92 (t,
2
J¼125 Hz); 32.87 (tm, J¼125 Hz); 41.27 (tm, J¼135 Hz);
J¼140 Hz); 54.01 (qd, J¼147, 4.9 Hz); 54.88 (qd, J¼147,
4.9 Hz); 63.18 (dm, J¼157 Hz); 67.06 (t, J¼142 Hz);
102.04 (dm, J¼161 Hz); 114.78 (dd, J¼159, 4.8 Hz, C-3,
C-5); 128.73 (ddd, J¼158, 7.3, 4.5 Hz, C-2, C-6); 130.88 (t,
J¼7.3 Hz, C-1); 159.42 (m, C-4); 171.39 (m); 172.54 (m,
CONH); HRMS, m/z: 411.1953 found (calcd for
4
4.44 (tm, J¼145 Hz); 46.20 (tm, J¼141 Hz); 61.01 (dm,
J¼157 Hz); 67.07 (t, J¼145 Hz); 114.79 (dd, J¼156,
5
.4 Hz, C-3, C-5); 127.83, 128.11, 129.03, 130.18 (m,
0
0
0
0
0
0
C-2, C-6, C-2 , C-3 , C-4 , C-5 , C-6 , C-1); 135.28 (m, C-1 );
59.47 (m, C-4); 172.44 (m, C-4, CO); 173.05 (m, CONH);
HRMS, m/z: 471.1953 found (calcd for C H N O S,
1
þ
C H N O S, [MþH] requires: 411.1954).
20 31 2 5
2
5
31
2
5
þ
[
MþH] requires: 471.1954).
4
.2.9. 4-[4-(3-Allyl-4-oxo-thiazolidin-2-yl)-phenoxy]-N-
1
4
.2.6. 4-[4-(3-Benzo[1,3]dioxol-5-ylmethyl-4-oxo-thiazo-
benzyl-butyramide (13i). Yield¼30%. H NMR (CDCl ,
3
lidin-2-yl)-phenoxy]-N-propyl-butyramide (13f). Yield¼
300 MHz) d 2.10 (quint, 2H, J¼6.5 Hz); 2.40 (t, 2H,
J¼7.4 Hz); 3.08 (dd, 1H, J¼15.3, 7.8 Hz); 3.69 (dd, 2H,
1
4
1
0%. H NMR (CDCl , 300 MHz) d 0.90 (t, 3H, J¼7.4 Hz);
3
.51 (sext, 2H, J¼7.2 Hz); 2.14 (quint, 2H, J¼6.9 Hz); 2.40
J¼35.6, 15.5 Hz, SCH ); 3.95 (t, 2H, J¼6 Hz); 4.37 (d, 2H,
2
(
t, 2H, J¼7.3 Hz); 3.21 (q, 2H, J¼7 Hz); 3.42 (d, 1H,
J¼5.6 Hz); 4.99 (dd, 1H, J¼17, 0.6 Hz, H ); 5.12 (m,
allyl
J¼14.6 Hz); 3.77 (dd, 2H, J¼24.5, 15.5 Hz, SCH ); 4.10 (t,
1H); 5.36 (d, 1H, J¼1.2 Hz); 5.15 (d, 1H, J¼9.1 Hz, Hallyl);
2
2
H, J¼6 Hz); 4.90 (d, 1H, J¼14.6 Hz); 5.36 (s, 1H); 5.93 (s,
H); 6.20 (broad t, 1H, J¼4.8 Hz, NH); 6.50–7.10 (m, 7H,
5.55 (s, 1H); 5.60 (m, 1H, H ); 6.78 (s large, 1H, NH);
allyl
2
6.83 (d, 2H, J¼8.6 Hz, H-3, H-5); 7.16–7.28 (m, 7H, Ar).
1
3
13
Ar). C NMR (CDCl , 75 MHz) d 11.50 (qt, J¼126,
C NMR (CDCl , 75 MHz) d 25.15 (tm, J¼130 Hz); 32.65
3
3
4
3
.1 Hz); 22.90 (tm, J¼126 Hz); 25.25 (tm, J¼126 Hz);
(tm, J¼129 Hz); 32.98 (t, J¼146 Hz, CH S); 43.46 (t,
2
2.70 (tm, J¼125 Hz); 33.10 (t, J¼146 Hz, CH S); 41.30
J¼138 Hz); 45.02 (tm, J¼139 Hz); 62.77 (dm, J¼156 Hz);
2
(
tm, J¼140 Hz); 45.80 (tm, J¼140 Hz); 62.42 (d,
67.07 (t, J¼144 Hz); 114.85 (dd, J¼160, 4.8 Hz, C-3, C-5);
J¼156 Hz); 67.19 (t, J¼144 Hz); 101.20 (t, J¼173 Hz);
118.86 (tt, J¼154 Hz, CH v); 127.36, 127.68, 128.62,
2
0
0
0
0
0
0
0
1
1
5
08.20 (d, J¼165 Hz, C-2 ); 108.72 (dm, J¼163 Hz, C-6 );
128.65 (m, C-2 , C-3 , C-4 , C-5 , C-6 , C-2, C-6);130.78 (t,
14.87 (d, J¼160 Hz, C-3, C-5); 121.88 (dq, J¼161,
J¼7.43 Hz, C-1); 131.07 (dm, J¼160 Hz, CHv); 138.46
0
0
HRMS, m/z: 411.1744 found (calcd for C H N O S,
.63 Hz, C-2, C-6); 128.78 (dm, J¼158 Hz, C-5 ); 129.09
(m, C-1 ); 159.50 (m, C-4); 170.84 (m); 172.42 (m, CONH);
0
47.96 (m, C-4 ); 159.53 (m, C-4); 171.02 (m); 172.29 (m,
0
(
1
m, C-1 ); 130.63 (t, J¼7.4 Hz, C-1); 147.26 (m, C-3 );
2
3 27 2 3
0
CONH); HRMS, m/z: 457.1787 found (calcd for
þ
[MþH] requires: 411.1742).
þ
C H N O S, [MþH] requires: 457.1797).
4.2.10. 3-Benzyl-2-[4-(4-oxo-4-piperidin-1-yl-butoxy)-
1
2
4 29 2 5
phenyl]-thiazolidin-4-one (14a). Yield¼26%. H NMR
4
.2.7. 4-[4-(3-Benzo[1,3]dioxol-5-ylmethyl-4-oxo-thiazo-
(CDCl , 300 MHz) d 1.45–1.65 (m, 6H); 2.11 (quint., 2H,
3
lidin-2-yl)-phenoxy]-N-benzyl-butyramide (13g). Yield¼
J¼6.9 Hz); 2.44 (t, 2H, J¼7.1 Hz); 3.38–3.53 (m, 5H); 3.76
1
3
9%. H NMR (CDCl , 300 MHz) d 2.14 (quint, 2H,
3
(dd, 2H, J¼38.7, 15.6 Hz, SCH ); 4.02 (t, 2H, J¼6 Hz);
2
J¼6.8 Hz); 2.43 (t, 2H, J¼7 Hz); 3.41 (d, 1H, J¼14.5 Hz);
5.08 (d, 1H, J¼15.6 Hz); 5.34 (s, 1H); 6.52–7.33 (m, 9H,
1
3
3
.76 (dd, 2H, J¼38.6, 15.6 Hz, SCH ); 4.02 (t, 2H,
Ar). C NMR (CDCl , 75 MHz) d 24.50, 24.89, 25.57,
3
2
J¼6 Hz); 4.98 (d, 1H, J¼14.6 Hz); 5.36 (d, 1H,
26.44, 29.39 (tm, J¼130 Hz); 33.09 (t, J¼145 Hz); 42.71
(tm, J¼137 Hz); 46.03 (tm, J¼139 Hz); 62.51 (dm,
J¼159 Hz); 67.27 (tm, J¼145 Hz); 114.91 (dd, J¼162,
4.7 Hz, C-3, C-5); 127.72, 127.91, 128.40, 128.84, 130.50
J¼1.2 Hz); 5.93 (s, 2H); 6.22 (br t, 1H, J¼5.6 Hz, NH);
1
3
6
2
.48–7.30 (m, 12H, Ar). C NMR (CDCl , 75 MHz) d
3
5.08 (tm, J¼130 Hz); 32.74 (tm, J¼125 Hz); 32.10 (t,
0
0
0
0
0
J¼146 Hz, CH S); 43.56 (tm, J¼137 Hz, CH Ar); 45.78
(m, C-2, C-6, C-2 , C-4 , C-5 , C-6 , C-1); 135.51 (m, C-1 );
159.59 (m, C-4); 170.46 (m, C-4, CO); 171.10 (m, CONH);
HRMS, m/z: 439.2053 found (calcd for C H N O S,
2
2
(
tm, J¼137 Hz, CH Ar); 62.36 (d, J¼144 Hz); 66.97 (t,
2
J¼145 Hz); 101.11 (t, J¼173 Hz); 108.19 (d, J¼164 Hz,
2
5 31 2 3
0
0
00
þ
C-2 ); 108.74 (dm, J¼162 Hz, C-6 ); 114.84 (d, J¼159 Hz,
[MþH] requires: 439.2055).
C-3, C-5); 121.90 (dq, J¼161, 6.5 Hz, C-2, C-6); 127.46,
0
0
0
0
0
1
27.60, 128.66, 128.69 (m, C-2 , C-3 , C-4 , C-5 , C-6 ,
4.2.11. 3-Benzyl-2-[4-(4-oxo-4-pyrrolidin-1-yl-butoxy)-
1
0
0
m, C-1 ); 147.24 (m, C-3 ); 147.94 (m, C-4 ); 159.44 (m,
0
C-5 );129.07 (m, C-1 ); 130.67 (t, J¼7.6 Hz, C-1); 138.24
phenyl]-thiazolidin-4-one (14b). Yield¼30%. H NMR
0
C-4); 171.00 (m); 172.11 (m, CONH); HRMS, m/z:
0
00
00
(
(CDCl , 300 MHz) d 1.83–1.91 (sext., 4H, J¼6.5 Hz); 2.13
3
(quint., 2H, J¼6.6 Hz); 2.45 (t, 2H, J¼7 Hz); 3.40–3.44 (t,
þ
5
5
05.1802 found (calcd for C H N O S, [MþH] requires:
4H, J¼6.7 Hz); 3.52 (d, 1H, J¼14.7 Hz); 3.78 (dd, 2H,
2
8 29 2 5
05.1797).
J¼35.5, 14.6 Hz, SCH ); 4.04 (t, 2H, J¼6.0 Hz); 5.10 (d,
2
1
3
1
H, J¼14.7 Hz); 5.35 (s, 1H); 6.90–7.35 (m, 9H, Ar).
C
4
.2.8. 4-{4-[3-(2,2-Dimethoxy-ethyl)-4-oxo-thiazolidin-2-
NMR (CDCl , 75 MHz) d 24.38 (tm, J¼129 Hz); 26.05 (tm,
3
yl]-phenoxy}-N-propyl-butyramide (13h). Yield¼47%.
J¼129 Hz); 30.73 (tm, J¼125 Hz); 33.08 (t, J¼145 Hz);

J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
6129
4
5.68 (tm, J¼140 Hz); 46.55 (tm, J¼139 Hz); 62.48 (dm,
Chem. Soc. 2002, 23, 667. (b) Leadbeater, N. E.; Torenius,
H. M. J. Org. Chem. 2002, 67, 3145. (c) Ley, S. V.; Leach,
A. G.; Storer, R. I. J. Chem. Soc., Perkin Trans. 1 2001, 358.
9. Giguere, R. J.; Bray, T. L.; Duncan, S. M. Tetrahedron Lett.
1986, 27, 4945.
10. For reviews, see: (a) Lidstr o¨ m, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225. (b) de la Hoz, A.;
Diaz-Ortis, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem.
2000, 3659. (c) Varma, R. S. Green Chem. 1999, 1, 43. (d)
Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Math e´ , D. Synthesis 1998, 1213. (e) Caddick,
S. Tetrahedron 1995, 51, 10403. (f) Strauss, C. R.; Trainor,
R. W. Aust. J. Chem. 1995, 48, 1665.
J¼155 Hz); 62.70 (tm, J¼144 Hz); 114.89 (dd, J¼163 Hz,
C-3, C-5); 127.70, 127.86, 128.35, 128.73 (m, C-2, C-6,
C-2 , C-3 , C-4 , C-5 , C-6 ); 130.50 (m, C-1); 135.36 (m,
0
0
C-1 ); 159.58 (m, C-4); 170.76 (m, C-4, CO); 171.06
0
0
0
0
CONH); HRMS, m/z: 425.1905 found (calcd for
(
þ
C H N O S, [MþH] requires: 425.1899).
2
4 29 2 3
4
.2.12. 3-Benzyl-2-[4-(4-oxo-4-morpholin-1-yl-butoxy)-
1
phenyl]-thiazolidin-4-one (14c). Yield¼25%. H NMR
(
2
CDCl , 300 MHz) d 2.13 (quint., 2H, J¼6.1 Hz); 2.43–
3
.50 (t, 2H, J¼7.2 Hz); 3.41–3.65 (m, 9H); 3.75 (dd, 2H,
J¼38.8, 15.6 Hz, SCH ); 3.98–4.02 (t, 2H, J¼6 Hz); 5.08
2
(
d, 1H, J¼14.7 Hz); 5.33 (s, 1H); 6.87 (d, 2H, J¼8.6 Hz, H-
11. For reviews, see: (a) Lew, A.; Krutzik, P. O.; Hart, M. E.;
Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95. (b) Wathey,
B.; Thierney, J.; Lidstr o¨ m, P.; Westman, J. Drug Discov.
Today 2002, 7, 373. (c) Larhed, M.; Hallberg, A. Drug Discov.
Today 2001, 6, 406. (d) Kappe, C. O. Am. Lab. 2001, 13.
12. (a) Stradler, A.; Kappe, C. O. Eur. J. Org. Chem. 2001, 919.
(b) Stradler, A.; Kappe, C. O. Tetrahedron 2001, 57, 3915. (c)
Kumar, H. M. S.; Ajaneyulu, S.; Reddy, B. V. S.; Yadav, J. S.
Synlett 2000, 1129. (d) Hoel, A. M. L.; Nielsen, J. Tetrahedron
Lett. 1999, 40, 3941. (e) Yu, H. M.; Chen, S. T.; Wang, K. T.
J. Org. Chem. 1992, 57, 4781.
1
3
3
7
3
, H-5); 7.05–7.30 (m, 7H, Ar). C NMR (CDCl ,
3
5 MHz) d 25.16 (tm, J¼127 Hz); 32.63 (tm, J¼127 Hz);
3.06 (t, J¼145 Hz); 43.44 (tm, J¼140 Hz); 46.02 (t,
J¼140 Hz); 62.47 (dm, J¼156 Hz); 66.80 (tm, J¼144 Hz);
6
C-5); 127.32, 127.69, 127.89, 128.34 (m, C-2, C-6, C-2 , C-
7.11 (tt, J¼145, 4.4 Hz); 114.88 (dd, J¼163, 4.4 Hz, C-3,
0
0
0
0
0
0
3
, C-4 , C-5 , C-6 ); 130.66 (m, C-1); 138.56 (m, C-1 );
59.51 (m, C-4); 170.91 (m, C-4, CO); 172.38 (CONH);
1
HRMS, m/z: 441.1850 found (calcd for C H N O S,
2
4 29 2 4
þ
[
MþH] requires: 441.1848).
1
3. (a) Grotli, M.; Grotfredsen, C. H.; Rademann, J.; Bucharett, J.;
Clark, A. J.; Duus, J. P.; Meldal, M. J. Comb. Chem. 2000, 2,
1
08. (b) Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J.
Acknowledgements
Tetrahedron Lett. 2000, 41, 6371. (c) Blettner, C. G.; Konig,
W. A.; Stenzel, W.; Shotten, T. J. Org. Chem. 1999, 64, 3885.
4. (a) Bazureau, J. P.; Hamelin, J.; Texier-Boullet, F. Microwave
in organic synthesis. In Microwave in Heterocyclic Chemistry;
First Edition. Loupy, A., Ed.; Wiley–VCH: Weinheim, 2002;
Chapter 4. (b) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron
Lett. 2000, 41, 7351. (c) Fraga-Dubreuil, J.; Bourhala, K.;
Rahmouni, M.; Bazureau, J. P.; Hamelin, J. Catal. Commun.
2002, 3, 185.
One of us (J. F. D.) thank the ‘Minist e` re de la Recherche et
de l’Enseignement Sup e´ rieur’ for the research fellowship.
The authors thank also Professor Jack Hamelin for fruitful
discussions.
1
References
1
5. Murphy, V.; Hagemeyer, A.; Poojary, D. Patent WO 032,572
A2, June 8, 2000.
1
2
. Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.;
Wiley–VCH: Weinheim, 2002.
. (a) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35,
16. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett. 2000, 42,
6097.
6
86. (b) Ritter, S. K. Chem. Eng. News 2001, 79, 27. (c)
17. (a) Liu, H.; Li, Z.; Anthansen, T. Molecules 2000, 5, 1055. (b)
Lakhan, R. Agric. Biol. Chem. 1981, 46, 557.
18. G u¨ rsoy, A.; Terzioglu, N.; Ot u¨ k, G. Eur. J. Med. Chem. 1997,
32, 753.
Anastas, P. T.; Worner, J. C. Green Chem. 2000, 2, 289.
. For reviews, see: (a) Dupont, J.; de Souza, R. F.; Suarez, P. A.
Z. Chem. Rev. 2002, 102, 3667. (b) Welton, T. Chem. Rev.
3
1
999, 99, 3667. (c) Gordon, C. M. Appl. Catal. A 2001, 222,
01. (d) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A:
19. (a) Goel, B.; Ram, T.; Tyagi, R.; Bansal, E.; Kumar, A.;
Mukherjee, D.; Sinha, J. N. Eur. J. Med. Chem. 1999, 34, 265.
(b) Walhand, D. A.; Uwaydah, I. M. US Patent 5,061,720,
October, 29, 1991.
1
Chem. 2002, 182–183, 419.
4
. (a) Chauvin, Y.; Olivier, H. Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Herrmann,
W. A., Eds.; Wiley-VCH: New York, 1996; Vol. 1, p 245. (b)
Chauvin, Y.; de Souza, R. F.; Olivier, H. US Patent 5,723,712,
20. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron Lett.
2000, 41, 5147, and references cited therein.
21. Fraga-Dubreuil, J.; Famelart, M. H.; Bazureau, J. P. Org.
Process. Res. Dev. 2002, 6, 374.
1996; Chem. Abstr. 1999, 126, 173356u. (c) Freemantle, M.
Chem. Eng. News 1998, 76, 32.
22. Westmann, J. Personal Chemistry, Upsala (SE), WO 00/72956
A1, 2000.
5
6
. Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000, 39,
3
. (a) Advances in Molten Salt Chemistry; Mamamtov, G.,
773.
23. (a) Commarmot, R.; Didenot, R.; Gardais, J. F. Fr. Demande
1985, 560, 529. Chem. Abstr. 1986, 105, 17442. (b) For
description of commercial microwave devices available with
adequate mixing and control of reaction parameters, see sites:
http://www.cem.com and http://www.personalchemistry.com.
24. Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67,
3145.
Mamantov, C., Eds.; Elsevier: New York, 1983; Vols. 5 and 6.
(
b) Hussey, C. L. Pure Appl. Chem. 1988, 60, 1763. (c)
Seddon, K. R. In Molten Salt Chemistry. Mamantov, G.,
Marassi, R., Eds.; Reidel: Dordrecht, 1987; p 365.
. Prinz, T.; Keim, W.; Driessen-H o¨ llscher, B. Angew. Chem. Int.
Ed. Engl. 1996, 35, 1708.
7
8
25. Munson, M. C.; Cook, A. W.; Josey, J. A.; Rao, C.
Tetrahedron Lett. 1998, 39, 7223.
. (a) Lee, S.-gi.; Lee, J. K.; Song, C. E.; Kim, D. C. Bull. Korean

6130
J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron 59 (2003) 6121–6130
2
6. (a) Cook, G. C.; Schullek, J. R.; Holmes, C. P.; Chinn, J. P.;
Gordon, E. M.; Gallop, M. A. Biorg. Chem. Lett. 1996, 6, 701.
32. Imric, C.; Elogo, E. R. T.; Mc Cleland, C. W.; Williams, W.
Green Chem. 2002, 4, 159.
(
b) Holmes, C. P.; Chinn, J. P.; Cook, G. C.; Gordon, E. M.;
33. Varma, R. S.; Naicher, K. P. Tetrahedron Lett. 1999, 40, 6177,
and references cited therein.
Gallop, M. A. J. Org. Chem. 1995, 60, 7328.
7. Hullar, T. L.; Failla, D. L. J. Med. Chem. 1969, 12, 420.
8. Buckle, D. R.; Fenwick, A. E.; Outred, D. J.; Rockell, C. J. M.
J. Chem. Res. (M) 1987, 12, 3144.
2
2
34. Perreux, L.;Loupy, A.; Volatron, F. Tetrahedron2002, 58, 2155.
35. Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
3
6. Part of this work was presented at ‘Le Defi des Nouvelles
´
2
9. Brown, S. J. Am. Chem. Soc. 1959, 81, 2532.
0. (a) Stradler, A.; Kappe, C. O. Tetrahedron 2001, 57, 3915. (b)
Mathias, L. J. Synthesis 1979, 561.
´
´
Technologies en Chimie Moleculaire’, Universite de Rennes
, Campus de Beaulieu, France, April 15–18 2002, Abstracts,
CO-8, see site http://ntc2002.univ-rennes1.fr.
3
1
3
1. Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129.