Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the three component preparation of 2-thioxo tetrahydropyrimidin-4-(1H)-ones under microwave dielectric heating

Article abstract of DOI:10.1016/j.tet.2004.03.026

An ionic liquid phase organic synthesis (IoLiPOS) has been developed for the preparation of 2-thioxo tetrahydropyrimidin-4(1H)-ones. Treatment of the starting poly(ethyleneglycol)ionic liquid phases (PEG_n-ILPs) 1 with acryloyl chloride 2 afforded a serie of (PEG_n)-ILPs bound acrylate 3 in quantitative yields. Michael addition of aliphatic primary amines 5 to the PEG₁-ILPs 3(a,d) allowed the preparation of β-aminoesters 6 in high yields. Addition of alkyl isothiocyanates 7 to 6 gave the corresponding thioureido esters 8 in the third step. The final cyclization-cleavage under microwave/solventless strategy provides, under basic conditions, the expected 2-thioxo tetrahydropyrimidin-4(1H)-ones 9 in high purity after flash chromatography. According to the IoLiPOS methodology, the NMR method was used to establish loading of all the PEG-ionic liquid phases intermediates.

Full text of DOI:10.1016/j.tet.2004.03.026

Tetrahedron 60 (2004) 3745–3753
Ionic liquid phase organic synthesis (IoLiPOS) methodology
applied to the three component preparation of 2-thioxo
tetrahydropyrimidin-4-(1H)-ones under microwave
dielectric heating
Halima Hakkou,a Jean Jacques Vanden Eynde,b Jack Hamelina and Jean Pierre Bazureaua
,
*
a
´ ` ` ˆ
Universite de Rennes 1, Institut de Chimie, Synthese & Electrosynthese Organiques 3, UMR 6510, Bat. 10A, Campus de Beaulieu,
CS 74205, (F) 35042 Rennes Cedex, France
bXavier University of Louisiana, College of Pharmacy, Department of Basic Pharmaceutical Sciences,
1 Drexel Drive, New Orleans, LA 70125, USA
Received 9 December 2003; revised 4 March 2004; accepted 5 March 2004
Abstract—An ionic liquid phase organic synthesis (IoLiPOS) has been developed for the preparation of 2-thioxo tetrahydropyrimidin-
4(1H)-ones. Treatment of the starting poly(ethyleneglycol)ionic liquid phases (PEGn-ILPs) 1 with acryloyl chloride 2 afforded a serie of
(PEGn)-ILPs bound acrylate 3 in quantitative yields. Michael addition of aliphatic primary amines 5 to the PEG1-ILPs 3(a,d) allowed the
preparation of b-aminoesters 6 in high yields. Addition of alkyl isothiocyanates 7 to 6 gave the corresponding thioureido esters 8 in the third
step. The final cyclization-cleavage under microwave/solventless strategy provides, under basic conditions, the expected 2-thioxo
tetrahydropyrimidin-4(1H)-ones 9 in high purity after flash chromatography. According to the IoLiPOS methodology, the NMR method was
used to establish loading of all the PEG-ionic liquid phases intermediates.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
high compatibility and good swelling characteristic with a
wide range of non-polar solvents.9 Nevertheless these resins
fail when polar solvents are needed due to hindered
accessibility to the reactive sites.10 Soluble-polymer
supported syntheses have recently emerged as an alternative
and powerful technique for the preparation of heterocyclic
libraries.11 Modification of solid surfaces of solid resins
(MR) with polar and soluble polymers such as poly
(ethyleneglycol) PEG-derivatives can achieve several func-
tions depending on the use of the resulting hybrid polymer.
Combinatorial chemistry and high-throughput parallel
synthesis have emerged as a powerful technique for the
discovery of new pharmaceutical lead compounds.1 The
focus of this research field, which initially involved the
synthesis, of peptides and oligonucleotides, is now extended
to the synthesis of small heterocyclic molecules with solid
phase.2 Heterocycles, such as 4H-imidazolones,3 benzo-
diazepines,4 pyrrolidines,5 2-arylamino benzimidazoles,6
bicyclic guanidines7 have received special attention in
combinatorial synthesis for their biological relevant proper-
ties.8 This strategy has permitted the rapid synthesis of large
number of organic molecules in a short period, facilitating
their use in high-throughput screening. The initial efforts
were focused on the use of solid phase organic synthesis
(SPOS) by taking advantage of simple filtration techniques
to wash off the excess reagents and by-products from the
desired polymer-bound product. The use of cross-linked
polystyrene based resins, such as Merrifield resin (MR) in
combinatorial synthesis, is important due to their stability,
Such hybrid polymers can combine some of the advantages
of both types of polymers such as the physical stability of
insoluble polymers that allows different substrates to
approach the reactive sites more efficiently and hence
increases the reaction rates. Liquid phase combinatorial
synthesis offers several unique advantages: reactions may
be carried out in homogeneous solution, the large excess of
reagents typically used in solid-supported synthesis is
normally not required in liquid phase organic synthesis.
Characterisation of immobilized intermediates is also
straightforward because the soluble polymer support does
not interfere with spectroscopic methods.
Keywords: Ionic liquid; Tetrahydropyrimidinones; Cyclization-cleavage;
Acrylate; Michael addition; Microwave; Solvent-free conditions.
The use of microwave irradiation (mv) as an alternative
mode of heating reaction mixtures has been observed to
*
Corresponding author. Tel.: þ33-2-23-23-66-03; fax: þ33-2-23-23-63-
74; e-mail address: jean-pierre.bazureau@univ-rennesl.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.026

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H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
Figure 1. Poly(ethyleneglycol)-ionic liquid matrices used for ionic liquid phase organic synthesis (IoLiPOS).
dramatically reduce reaction times and affect product ratios
and yields.12 It is clear that the application of microwave
technology to rapid synthesis of biologically significant
molecules on solid phases, liquid phases or hybrid polymers
would be of great value for library generation. This
technology has recently been recognized as a useful tool
for a drug-discovery program.13
with some other polar solvents (acetone, ethyl acetate,
acetonitrile). This turnable miscibility can be used to
separate reaction by-products from the supported products
and the primary advantage of the PEG-ILPs is that
optimized reaction conditions were performed using
standard analytical methods (NMR, TLC).
In connection with our research program on exploitation of
the PEG-ILPs as tools in ‘liquid phase organic synthesis’
(LPOS), we choose to explore now the 2-thioxo
tetra hydropyrimidinone moiety as new heterocyclic scaf-
fold. In our approach, the 2-thioxo tetrahydropyrimidin-
4(1H)-one scaffold can be built from a primary amine, an
isothiocyanate and a b-dielectrophile (Fig. 2), and the
carboxylic function is used as the site of attachment to the
liquid support. As a suitable model reaction for ionic liquid-
phase supported organic synthesis, we have chosen to use
acrylate bound to the ionic liquid moiety (from commercial
Recently, we have reported the use of task-specific ionic
liquids (Fig. 1) as a synthetic equivalent of liquid phase
matrices for the preparation of a small library of 4-thiazo-
lidinones.14 According to this ‘ionic liquid phase organic
synthesis (IoLiPOS)’ methodology, it was possible to bind
the heterocyclic scaffold to the PEG-ionic liquid phases
(PEG-ILPs) by a one pot three component condensation. We
have observed that the grafted PEG-ILPs are immiscible
with low polarity solvents (hexane, toluene) and with some
polar solvents (diethyl ether, tetrahydrofuran) but miscible
Figure 2. Components for the synthesis of 2-thioxo tetrahydropyrimidin-4(1H)-ones.
Scheme 1. Reagents and reaction condition: (i) 2 (1.2 equiv.), DCM, reflux, 48 h. (ii) 5 (1 equiv.), MeCN, 25 8C, 24 h. (iii) 7 (1 equiv.), MeCN, 18 h. (iv) DEA
(2 equiv.), mv, 120 8C (power¼20%), 15–45 min then purification by flash chromatography on silica gel 60F 254 (Merck).

H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
3747
acryloyl chloride in the first step) as novel task specific ionic
liquid. We describe herein the general ionic liquid phase
organic synthesis of 2-thioxo tetrahydropyrimidin-4(1H)-
ones.
yellow acrylate-ILPs 3 were further dried under high
vacuum (1022 Torr) at 60 8C for 1 h (Table 1). The ILPs
were characterized by mass spectrometry and proton NMR,
confirming that the major compound has a molecular ion
corresponding to the acrylate-ILPs 3.
With the desired acrylate-ILPs 1 in hand, we have examined
the Michael addition of various monosubstituted alkyl
amines in the second step to the PEG1-ILPS 1(a,b) with BF4
and PF6 as the corresponding coordinating anions. An array
of experiments carried out with different reaction tempera-
tures revealed that the optimal results were obtained at
25 8C after 24 h. A stoichiometry of 1:1 of IL-phase 1:
amine 5 gave successful regioselective addition of mono-
substituted amine into the IL-phase 1 in dry stirred
acetonitrile. Progress of the Michael addition was monitored
(after elimination of the solvent) by proton NMR spectro-
scopy which is faster and more convenient than conven-
tional methods used in solid phase organic synthesis (SPOS)
that require the concentration of cleaved material. We have
also found that the b-amino esters 6 were prepared in
quantitative yields (Table 2) and with our method, it was not
necessary to use large excess of amine 5 as described in the
literature with a resin-bound acrylate.
2. Results and discussion
In order to explore the application of the [PEGn-mim][X]
115 (n¼1, 2, 3 and X¼BF4, PF6) as a new class of soluble
supports, we were first focused on the preparation of simple
acrylates derivatives16 from the PEG-ILPs 1 (Scheme 1).
Under neat reaction conditions, treatment of the PEG-ILPs 1
with acryloyl chloride 2 at 70 8C provided the expected
acrylate-ILPs 3 along with hydrogen chloride addition
products 417 in a 4:1 ratio. In an effort to avoid this problem,
attention was turned to selective method for the preparation
of acrylate-ILPs 3. After exploring a few sets of reaction
conditions, the one that proved to be most effective was the
addition of acryloyl chloride 2 to a diluted solution of PEG-
ILP 1 in dichloromethane at room temperature, followed by
a moderate heating at 40 8C for 48 h. The HCl by-product
formed in the reaction was removed by a stream of nitrogen
and was eventually dissolved in deionized water at 0 8C.
The acid aqueous solution was monitored by titration with
sodium hydroxide. After the work-up, the crude mobile pale
In the third step, addition of 1 equiv. of isothiocyanate 7 (7a:
R¼Me, 7b: R¼Bu) to the b-amino ester 6 bound to the ionic
liquid moiety in dry acetonitrile was generally completed in
24 h. Progress of the reaction of 6 with isothiocyanate 7 was
Table 1. Results of addition of acryloyl chloride 2 on PEGn-ionic liquid
phases 1(a-f) for the preparation of ILP bound acrylates 3(a-f)
1
also monitored by H NMR (or by TLC with CH2Cl2 as
eluent). As can be seen from Table 3, the ILP bound
thioureas 8 were prepared in high yields (96–98%)
according to this method. Similarly, when phenylisothio-
cyanate 7c was used, no reaction occurred in refluxing
MeCN and only the decomposition of the products was
observed when the reaction conditions were forced (neat
conditions, 70 8C, 7 days). During the experiments, it should
be noted that the thioureas 8 slowly glassify at room
temperature and were fully reliquified by mild heating at
70–80 8C. It is noteworthly that the ILP bound thioureas 8
appear to be stable at room temperature for several weeks.
Starting [PEGnmim][X]
ILP bound acrylate
Yield (%)b
Product 1
na
X
3
1a
1b
1c
1d
1e
1f
1
2
3
1
2
3
PF6
PF6
PF6
BF4
BF4
BF4
3a
3b
3c
3d
3e
3f
98
98
94
96
96
96
Consistent cyclization/cleavage of the thioureido esters 8 to
2-thioxo tetrahydropyrimidin-4(1H)-ones 9 was achieved
by treatment of the ILPs 8 with 2 equiv. of diethyl amine
a
Number of polyethyleneglycol (PEG) unit.
Yield of isolated product.
b
Table 2. Results for the preparation of b-amino esters 6(a-f) by Michael addition of amine 5(a-c) on the PEG1-ionic liquid phases 3a and 3d
Starting amine 5
Starting acrylate 3
Product 3
b-Amino ester 6
Yield of 6 (%)a
Product 5
R1
X
Product 6
5a
5b
5c
5a
5b
5c
Ph-CH2
iPr-CH2
Pr
Ph-CH2
iPr-CH2
Pr
3a
3a
3a
3d
3d
3d
PF6
PF6
PF6
BF4
BF4
BF4
6a
6b
6c
6d
6e
6f
98
96
96
94
94
96
a
Yield of isolated product.

3748
H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
Table 3. Results for the preparation of thioureido esters 8(a-h) from isothiocyanates 7(a,b) and b-aminoesters 6(a-f)
Starting b-aminoester 6
Starting isothiocyanate 7
Thioureido ester 8
Yield of 8 (%)a
Product 6
X
R1
Product 7
R2
Product 8
6a
6b
6c
6b
6d
6e
6f
PF6
PF6
PF6
PF6
BF4
BF4
BF4
BF4
Ph-CH2
iPr-CH2
Pr
iPr-CH2
Ph-CH2
iPr-CH2
Pr
7a
7a
7a
7b
7a
7a
7b
7b
Me
Me
Me
Bu
Me
Me
Me
Bu
8a
8b
8c
8d
8e
8f
94
96
98
90
94
96
96
94
8g
8h
6e
iPr-CH2
a
Yield of isolated product.
(DEA) when the reaction mixture was exposed to
microwave irradiation18 with the specified reaction time
(15 or 45 min) at 120 8C using solvent-free reaction
conditions (Table 4). On completion of the reaction, as
isolation is routine and the reactions are high yielding. The
use of [PEG1mim] [X] as novel IL phase in liquid phase
organic synthesis (LPOS) offers considerable advantages
because the side product is removed by simple extraction
and washings from the cleaved IL phase. In contrast to the
various restrictions of reaction development in solid phase
synthesis, IL phases allow standard analytical methods
(NMR, TLC) to monitor reaction progress. To our knowl-
edge, the ionic liquid phase organic synthesis (IoLiPOS)
methodology has never been reported for the preparation of
these 2-thioxo tetrahydropyrimidin-4(1H)-ones and may
complement those existing in the literature.21 We are
currently exploring the scope and potential of the ILPs by
extending this methodology to other heterocyclic targets.
Further applications of multicomponent multistep syntheses
of heterocycles will be reported in due course.
1
evidenced by H NMR, the crude reaction mixture was
extracted with chloroform (1:5 w/v) and the subsequent
flash chromatography purification on silica gel 60F 254
(Merck) afforded the desired 2-thioxo tetrahydropyrimidin-
4(1H)-ones 9(a-d) using CHCl3 or AcOEt as eluent. The
yields of isolated compounds 9(a-d) are quite respectable
(67–85%) and their purity has been established by
1
acquisition of clean H and 13C NMR as well as by FAB-
MS.
3. Conclusion
In summary, we report an efficient and new route to the
synthesis of 2-thioxo tetrahydropyrimidin-4(1H)-ones19
using the ionic liquid phase organic chemistry. Conjugate
addition of a primary amine to the PEG1-ionic liquid phase
bound unsaturated ester 3 gave the N-substituted b-amino
ester 6, which was further treated with an alkyl isothio-
cyanate 7 to produce the b-thioureido ester 8. Cleavage of 8
in basic media using solventless reaction conditions under
microwave irradiations20 gave cyclization of 8. Product
4. Experimental
4.1. General
Thin-layer chromatography (TLC) was accomplished on
0.2-mm precoated plates of silica gel 60 F-254 (Merck).
Visualisation was made with ultraviolet light (254 and
365 nm) or with a fluorescence indicator. For preparative
Table 4. 2-Thioxo tetrahydropyrimidin-4(1H)-ones 9(a-d) prepared from the thioureido esters 8(a-h) by cyclization/cleavage under microwave irradiations
(mv) at 120 8C using solvent-free reaction conditions
Product 9
R1
R2
Reaction time (min)
Yield of 9 (%)a
9a
9b
9c
9d
Ph-CH2
iPr-CH2
iPr-CH2
Pr
Me
Me
Bu
45
15
15
15
85
72
67
83
Me
a
Yield of isolated product after purification by chromatography on silica gel 60F 254 (Merck).

H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
3749
column chromatography, silica gel 60F 254 Merck (230–
240 mesh ASTM) was used. 1H NMR spectra were recorded
on BRUKER AC 300 P (300 MHz) spectrometer, 13C NMR
spectra on BRUKER AC 300 P (75 MHz) spectrometer.
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,
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
J¼1.6 Hz); 7.8 (t, 1H, J¼1.7 Hz); 9.06 (s, 1H). 13C NMR
(acetone d 6, 75 MHz) d 36.7 (q, J¼144 Hz); 49.4 (t, J¼
146 Hz); 63.5 (tm, J¼152 Hz); 123.9 (dm, J¼204 Hz);
124.8 (dm, J¼204 Hz); 128.5 (ddd, J¼164, 9.6, 2.6 Hz);
132.5 (dd, J¼165, 16 Hz); 138.2 (dm, J¼223 Hz), 166.0
(Sm, CO). HRMS, m/z: 181.0974 found (Calcd for
C9H13N2O2, Cþ requires: 181.0977).
4.2.2. 1-[2-(2-Acryloyloxy-ethoxy)ethyl]-3-methyl-imi-
dazolium hexafluorophosphate (3b). Yield¼98%. 1H
NMR (acetone d 6, 300 MHz) d 3.77 (t, 2H, J¼4 Hz); 3.92
(t, 2H, J¼4.8 Hz); 4.03 (s, 3H); 4.30 (t, 2H, J¼4.6 Hz); 4.52
(t, 2H, J¼4.8 Hz); 5.93 (dd, 1H, J¼10.3, 1.7 Hz); 6.15 (dd,
1H, J¼17.3, 1.3 Hz); 6.35 (dd, 1H, J¼17.3, 1.7 Hz); 7.66 (t,
1H, J¼1.5 Hz); 7.68 (t, 1H, J¼1.8 Hz); 8.92 (s, 1H). 13C
NMR (acetone d 6, 75 MHz) d 35.5 (q, J¼144 Hz); 49.1 (t,
J¼144 Hz); 62.9 (t, J¼148 Hz); 68.2 (tm, J¼145 Hz); 68.4
(tm, J¼143 Hz); 122.7 (dm, J¼203 Hz); 123.2 (dm, J¼
202 Hz); 128.2 (dm, J¼171 Hz); 130.6 (tm, J¼161 Hz);
136.8 (dm, J¼222 Hz), 205.8 (s, CO). HRMS, m/z:
225.1245 found (Calcd for C11H17N2O2, Cþ requires:
225.1239).
´
Regional de Mesures Physiques de l’Ouest (CRMPO,
Rennes). Reactions under microwave irradiations were
realized in the Synthewavew 402 reactor22 (Merck Eurolab,
Div. Prolabo, France). Acetonitrile was distilled over
calcium chloride after standing overnight and stored over
˚
molecular sieves (3 A). 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 [PEGn-mim][X] ionic
liquid phase 1 were synthetized according to our previous
method14 for 1-(2-hydroxy-ethyl)-3-methyl-imidazolium
hexafluorophosphate [PEG1mim][PF6] 1a, 1-(2-hydroxy-
ethyl)-3-methyl-imidazolium tetrafluoroborate [PEG1mim]-
[BF4] 1b, 1-[2-(2-hydroxy-ethoxy)-ethyl]-3-methyl-imida-
zolium hexafluorophosphate [PEG2mim][PF6] 1c, 1-[2-(2-
hydroxy-ethoxy)-ethyl]-3-methyl-imidazolium tetrafluoro-
borate [PEG2mim][BF4] 1d, 1-{2-[2-(2-hydroxy-ethoxy)-
ethoxy]-ethyl}-3-methyl-imidazolium hexafluorophosphate
[PEG3mim][PF6] 1e, 1-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-
ethyl}-3-methyl-imidazolium tetrafluoroborate [PEG3mim]-
[BF4] 1f.
4.2.3. 1-{2-[2-(2-Acryloyloxy-ethoxy-ethoxy]ethyl}-3-
methyl-imidazolium hexafluorophosphate (3c). Yield¼
94%. 1H NMR (acetone d 6, 300 MHz) d 3.57 (m, 2H); 3.64
(s, 2H); 3.72 (m, 2H); 3.84 (t, 2H, J¼4.8 Hz); 3.85 (s, 3H);
4.25 (m, 2H); 4.31 (t, 2H, J¼4.4 Hz); 5.92 (dd, 1H, J¼10,
1.2 Hz); 6.12 (dd, 1H, J¼17.3, 10.4 Hz); 6.36 (dd, 1H, J¼
17.3, 1.2 Hz); 7.36 (t, 1H, J¼1.7 Hz); 7.44 (t, 1H, J¼
1.8 Hz); 8.64 (s, 1H). 13C NMR (D2O, 75 MHz) d 34.9 (q,
J¼144 Hz); 48.2 (t, J¼144 Hz); 63.2 (t, J¼149 Hz); 67.6 (t,
J¼145 Hz); 68.8 (tm, J¼143 Hz); 121.8 (dm, J¼204 Hz);
122.7 (dm, J¼203 Hz); 126.7 (tm, J¼157 Hz); 133.5 (dm,
J¼226 Hz); 167.4 (sm, CO). HRMS, m/z: 269.1504 found
(Calcd for C13H21N2O2, Cþ requires: 269.15.01).
4.2. General procedure for acylation of the PEGn-ILPs
1(a-f)
A typical experimental procedure is as follows for 3b. To a
vigorously stirred solution of 1-(2-hydroxyethyl)-3-methyl-
imidazolium tetrafluoroborate [PEG1mim][BF4] 1b (2 g,
9.35 mmol, 1 equiv.) in dry dichloromethane (20 mL) was
added dropwise over 15 min at room temperature a solution
of commercial acryloyl chloride 2 (1.02 g, 11.26 mmol,
1.2 equiv.) in dry methylene chloride (10 mL). Then the
reaction mixture was refluxed at 40 8C during 48 h and the
HCl by-product formed during the reaction was distilled out
of the condenser. When the formed HCl had been
completely removed, the solution was cooled to room
temperature and CH2Cl2 was evaporated with a rotary
evaporator. Then the crude acrylate 3b was washed with
ether (3£10 mL) or AcOEt (3£10 mL) under magnetic
stirring. After decantation, the residual solvent was
eliminated in vacuo. The ionic liquid phase bound acrylate
3b was further dried under high vacuum (1022 Torr) at
60 8C for 8 h and lead to a pale yellow mobile ionic liquid
4.2.4. 1-(2-Acryloyloxy-ethyl)-3-methyl-imidazolium
tetrafluoroborate (3d). Yield¼96%. 1H NMR (acetone
d 6, 300 MHz) d 4.05 (s, 3H); 4.59 (t, 2H, J¼4.6 Hz); 4.73 (t,
2, J¼4.8 Hz); 5.93 (dd, 1H, J¼10, 1.6 Hz); 6.18 (dd, 1H,
J¼17, 10.3 Hz); 6.38 (dd, 1H, J¼17, 1.5 Hz); 7.69 (t, 1H,
J¼1.6 Hz); 7.8 (t, 1H, J¼1.7 Hz); 9.06 (s, 1H). 13C NMR
(acetone d 6, 75 MHz) d 36.7 (q, J¼144 Hz); 49.4 (t, J¼
146 Hz); 63.5 (tm, J¼152 Hz); 123.9 (dm, J¼204 Hz);
124.8 (dm, J¼204 Hz); 128.5 (ddd, J¼164, 9.6, 2.6 Hz);
132.5 (dd, J¼165, 16 Hz); 138.2 (dm, J¼223 Hz), 166.0
(Sm, CO). HRMS, m/z: 181.0974 found (Calcd for
C9H13N2O2, Cþ requires: 181.0977).
4.2.5. 1-[2-(2-Acryloyloxy-ethoxy)ethyl]-3-methyl-imi-
1
dazolium tetrafluoroborate (3e). Yield¼96%. H NMR
(acetone d 6, 300 MHz) d 3.77 (t, 2H, J¼4 Hz); 3.92 (t, 2H,
J¼4.8 Hz); 4.03 (s, 3H); 4.30 (t, 2H, J¼4.6 Hz); 4.52 (t, 2H,
J¼4.8 Hz); 5.93 (dd, 1H, J¼10.3, 1.7 Hz); 6.15 (dd, 1H,
J¼17.3, 1.3 Hz); 6.35 (dd, 1H, J¼17.3, 1.7 Hz); 7.66 (t, 1H,
J¼1.5 Hz); 7.68 (t, 1H, J¼1.8 Hz); 8.92 (s, 1H). 13C NMR
(acetone d 6, 75 MHz) d 35.5 (q, J¼144 Hz); 49.1 (t, J¼
144 Hz); 62.9 (t, J¼148 Hz); 68.2 (tm, J¼145 Hz); 68.4
(tm, J¼143 Hz); 122.7 (dm, J¼203 Hz); 123.2 (dm, J¼
202 Hz); 128.2 (dm, J¼171 Hz); 130.6 (tm, J¼161 Hz);
136.8 (dm, J¼222 Hz), 205.8 (s, CO). HRMS, m/z: 225.1245
found (Calcd for C11H17N2O2, Cþ requires: 225.1239).
1
phase in 98% yield which was controlled by H and 13C
NMR spectroscopy. It is advisable to handle the acrylate 3b
under inert atmosphere at 4 8C.
4.2.1. 1-(2-Acryloyloxy-ethyl)-3-methyl-imidazolium
hexafluorophosphate (3a). Yield¼98%. 1H NMR (acetone
d 6, 300 MHz) d 4.05 (s, 3H); 4.59 (t, 2H, J¼4.6 Hz); 4.73 (t,
2, J¼4.8 Hz); 5.93 (dd, 1H, J¼10, 1.6 Hz); 6.18 (dd, 1H,
J¼17, 10.3 Hz); 6.38 (dd, 1H, J¼17, 1.5 Hz); 7.69 (t, 1H,

3750
H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
4.2.6. 1-{2-[2-Acryloyloxy-ethoxy-ethoxy]ethyl}-3-methyl-
imidazolium tetrafluoroborate (3f). Yield¼96%. 1H NMR
(D2O, 300 MHz) d 3.57 (m, 2H); 3.64 (s, 2H); 3.72 (m, 2H);
3.84 (t, 2H, J¼4.8 Hz); 3.85 (s, 3H); 4.25 (m, 2H); 4.31
(t, 2H, J¼4.4 Hz); 5.92 (dd, 1H, J¼10, 1.2 Hz); 6.12 (dd,
1H, J¼17.3, 10.4 Hz); 6.36 (dd, 1H, J¼17.3, 1.2 Hz); 7.36
(t, 1H, J¼1.7 Hz); 7.44 (t, 1H, J¼1.8 Hz); 8.64 (s, 1H). 13C
NMR (D2O, 75 MHz) d 34.9 (q, J¼144 Hz); 48.2 (t, J¼
144 Hz); 63.2 (t, J¼149 Hz); 67.6 (t, J¼145 Hz); 68.8 (tm,
J¼143 Hz); 121.8 (dm, J¼204 Hz); 122.7 (dm, J¼203 Hz);
126.7 (tm, J¼157 Hz); 133.5 (dm, J¼226 Hz); 167.4 (sm,
CO). HRMS, m/z: 269.1504 found (Calcd for C13H21N2O2,
Cþ requires: 269.15.01).
4.3.3. 3-Methyl-1-[2-(3-propylamino-propionyloxy)-
ethyl]-imidazolium hexafluorophosphate (6c). Yield¼
1
96%. H NMR (acetone d 6, 300 MHz) d 0.88 (t, 3H, J¼
7.4 Hz); 1.50 (m, 2H, J¼7.3 Hz); 2.61 (t, 4H, J¼6.7 Hz);
2.91 (t, 2H, J¼6.5 Hz); 4.03 (s, 3H); 4.50 (t, 2H, J¼4.4 Hz);
4.63 (t, 2H, J¼4.3 Hz); 7.69 (d, 1H, J¼1.9 Hz); 7.8 (d, 1H,
J¼1.9 Hz). 13C NMR (acetone d 6, 75 MHz) d 12.1 (q, J¼
125 Hz); 23.1 (tm, J¼125 Hz); 34.6 (t, J¼126 Hz); 45.4 (t,
J¼133 Hz); 49.5 (t, J¼146 Hz); 60.8 (t, J¼145 Hz); 63.2 (t,
J¼150 Hz); 123.9 (dm, J¼204 Hz); 124.6 (dm, J¼204 Hz);
173 (sm, CO). HRMS, m/z: 240.1714 found (Calcd for
C12H22N3O2, Cþ requires: 240.1712).
4.3.4. 1-[2-(3-Benzylamino-propionyloxy)-ethyl]-3-
methyl-imidazolium tetrafluoroborate (6d). Yield¼
4.3. General procedure for Michael addition of alkyl-
amine 5 to the acrylate-ionic liquid phases 3a (X5PF6)
or 3d (X5BF4): synthesis of b-amino acrylate 6
1
94%. H NMR (acetone d 6, 300 MHz) d 2.60 (t, 2H, J¼
6.5 Hz); 2.88 (t, 2H, J¼7 Hz); 3.8 (s, 2H); 3.95 (s, 3H); 4.45
(m, 2H, J¼4.7 Hz); 4.62 (m, 2H, J¼4.7 Hz); 7.23–7.39 (m,
5H); 7.61 (d, 1H, J¼1.5 Hz); 7.75 (d, 1H, J¼1.6 Hz); 9.06
(s, 1H). 13C NMR (acetone d 6, 75 MHz) d 35.0 (t, J¼
126 Hz); 36.5 (q, J¼144 Hz); 45.1 (t, J¼133 Hz); 49.5 (t,
J¼146 Hz); 53.7 (tm, J¼171 Hz); 63.2 (t, J¼151 Hz); 123.9
(dm, J¼204 Hz); 124.6 (dm, J¼204 Hz); 127.8 (dm, J¼
159 Hz); 129.2 (dd, J¼160, 6.4 Hz); 129.7 (sm); 141.0 (dm,
J¼220 Hz); 170.3 (sm, CO). HRMS, m/z: 288.1714 found
(Calcd for C16H22N3O2, Cþ requires: 288.1712).
A solution of benzylamine 5a (0.59 g, 5.6 mmol) or iso-
butylamine 5b (0.402 g, 5.6 mmol) or propylamine 5c
(0.301 g, 5.6 mmol) in dry acetonitrile (20 mL) was added
dropwise over 20 min to a stirred solution of acrylate 3a
(1.81 g, 5.6 mmol) or 3b (1.49 g, 5.6 mmol) in dry
acetonitrile. After magnetic stirring at room temperature
for 24 h under inert atmosphere, the solvent was eliminated
in a rotary evaporator under reduced pressure. The crude
mobile b-amino acrylate 6 was washed three times with
AcOEt (10 mL) or ether (15 mL) with vigorous magnetic
stirring. After decantation, the residual solvent was removed
in vacuo. The ionic liquid phase bound b-amino acrylate 6
was further dried under high vacuum (1022 Torr) at 60 8C
for 8 h and lead to a pale yellow mobile ionic liquid phase in
4.3.5. 1-[2-(3-Isobutylamino-propionyloxy)-ethyl]-3-
methyl-imidazolium tetrafluoroborate (6e). Yield¼94%.
1H NMR (acetone d 6, 300 MHz) d 0.88 (d, 6H, J¼6.7 Hz);
1.71 (m, 1H, J¼6.7 Hz); 2.42 (d, 2H, J¼6.7 Hz); 2.60 (t,
2H, J¼6.6 Hz); 2.86 (t, 2H, J¼6.4 Hz); 4.04 (s, 3H); 4.49 (t,
2H, J¼5.2 Hz); 4.65 (t, 2H, J¼5.2 Hz); 7.70 (d, 1H, J¼
1.9 Hz); 7.81 (d, 1H, J¼1.9 Hz). 13C NMR (acetone d 6,
75 MHz) d 21.0 (qm, J¼125 Hz); 27.1 (dm, J¼125 Hz);
34.9 (t, J¼130 Hz); 36.7 (q, J¼144 Hz); 45.8 (t, J¼139 Hz);
49.5 (t, J¼147 Hz); 61.1 (t, J¼130 Hz); 63.2 (t, J¼151 Hz);
123.9 (dm, J¼204 Hz); 124.7 (dm, J¼204 Hz); 129.2 (dm,
J¼163 Hz); 173.2 (sm, CO). HRMS, m/z: 254.1867 found
(Calcd for C13H24N3O2, Cþ requires: 254.1869).
1
96–98% yield which was controlled by H and 13C NMR
spectroscopy. The b-amino acrylates 6 were stored under
inert atmosphere at 4 8C.
4.3.1. 1-[2-(3-Benzylamino-propionyloxy)-ethyl]-3-
methyl-imidazolium hexafluorophosphate (6a). Yield¼
98%. 1H NMR (acetone d 6, 300 MHz) d 2.60 (t, 2H,
J¼6.5 Hz); 2.88 (t, 2H, J¼7 Hz); 3.8 (s, 2H); 3.95 (s, 3H);
4.45 (m, 2H, J¼4.7 Hz); 4.62 (m, 2H, J¼4.7 Hz); 7.23–7.39
(m, 5H); 7.61 (d, 1H, J¼1.5 Hz); 7.75 (d, 1H, J¼1.6 Hz);
9.06 (s, 1H). 13C NMR (acetone d 6, 75 MHz) d 35.0 (t,
J¼126 Hz); 36.5 (q, J¼144 Hz); 45.1 (t, J¼133 Hz); 49.5 (t,
J¼146 Hz); 53.7 (tm, J¼171 Hz); 63.2 (t, J¼151 Hz); 123.9
(dm, J¼204 Hz); 124.6 (dm, J¼204 Hz); 127.8 (dm,
J¼159 Hz); 129.2 (dd, J¼160, 6.4 Hz); 129.7 (Sm); 141.0
(dm, J¼220 Hz); 170.3 (sm, CO). HRMS, m/z: 288.1714
found (Calcd for C16H22N3O2, Cþ requires: 288.1712).
4.3.6. 3-Methyl-1-[2-(3-propylamino-propionyloxy)-
ethyl]-imidazolium tetrafluoroborate (6f). Yield¼96%.
1H NMR (acetone d 6, 300 MHz) d 0.88 (t, 3H, J¼7.4 Hz);
1.50 (m, 2H, J¼7.3 Hz); 2.61 (t, 4H, J¼6.7 Hz); 2.91 (t, 2H,
J¼6.5 Hz); 4.03 (s, 3H); 4.50 (t, 2H, J¼4.4 Hz); 4.63 (t, 2H,
J¼4.3 Hz); 7.69 (d, 1H, J¼1.9 Hz); 7.8 (d, 1H, J¼1.9 Hz).
13C NMR (acetone d 6, 75 MHz) d 12.1 (q, J¼125 Hz); 23.1
(tm, J¼125 Hz); 34.6 (t, J¼126 Hz); 45.4 (t, J¼133 Hz);
49.5 (t, J¼146 Hz); 60.8 (t, J¼145 Hz); 63.2 (t, J¼150 Hz);
123.9 (dm, J¼204 Hz); 124.6 (dm, J¼204 Hz); 173 (sm,
CO). HRMS, m/z: 240.1714 found (Calcd for C12H22N3O2,
Cþ requires: 240.1712).
4.3.2. 1-[2-(3-Isobutylamino-propionyloxy)-ethyl]-3-
methyl-imidazolium hexafluorophosphate (6b). Yield¼
1
96%. H NMR (acetone d 6, 300 MHz) d 0.88 (d, 6H, J¼
6.7 Hz); 1.71 (m, 1H, J¼6.7 Hz); 2.42 (d, 2H, J¼6.7 Hz);
2.60 (t, 2H, J¼6.6 Hz); 2.86 (t, 2H, J¼6.4 Hz); 4.04 (s, 3H);
4.49 (t, 2H, J¼5.2 Hz); 4.65 (t, 2H, J¼5.2 Hz); 7.70 (d, 1H,
J¼1.9 Hz); 7.81 (d, 1H, J¼1.9 Hz). 13C NMR (acetone d 6,
75 MHz) d 21.0 (qm, J¼125 Hz); 27.1 (dm, J¼125 Hz);
34.9 (t, J¼130 Hz); 36.7 (q, J¼144 Hz); 45.8 (t, J¼139 Hz);
49.5 (t, J¼147 Hz); 61.1 (t, J¼130 Hz); 63.2 (t, J¼151 Hz);
123.9 (dm, J¼204 Hz); 124.7 (dm, J¼204 Hz); 129.2 (dm,
J¼163 Hz); 173.2 (sm, CO). HRMS, m/z: 254.1867 found
(Calcd for C13H24N3O2, Cþ requires: 254.1869).
4.4. Typical procedure for the synthesis of thioureido
esters 8(a-h) from isothiocyanates 7(a,b) and b-amino
esters 6(a-f)
A mixture of b-amino acrylate 6 (3.83 mmol) and
methylisothiocyanate 7a (0.28 g, 3.83 mmol) or butyliso-
thiocyanate 7b (0.44 g, 3.83 mmol) in dry acetontile
(25 mL) was stirred vigorously at room temperature under
nitrogen for 18 h. After removal of solvent in vacuo, the

H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
3751
crude reaction mixture was washed twice with AcOEt
(15 mL) under magnetic stirring. The washing solvent was
eliminated from the ionic liquid phase bound thioureido
ester 8 by decantation, and the resulting thioureido ester 8
was further dried under reduced pressure (1022 Torr) at
60 8C for 8 h to give the expected compound 8 as a nearly
J¼7.5 Hz); 3.52 (t, 2H, J¼7.4 Hz); 3.95 (s, 3H); 4.43 (t, 2H,
J¼5 Hz); 4.60 (t, 2H, J¼4.5 Hz); 7.71 (d, 1H, J¼1.6 Hz);
7.81 (d, 1H, J¼1.7 Hz); 9.09 (s, 1H). 13C NMR (acetone d 6,
75 MHz) d 13.95 (qm, J¼125 Hz); 18.9 (tm, J¼126 Hz);
19.9 (qm, J¼125 Hz); 26.9 (dm, J¼128 Hz); 30.6 (tm,
J¼125 Hz); 31.4 (tm, J¼132 Hz); 36.8 (q, J¼150 Hz); 45.8
(tm, J¼139 Hz); 49.5 (t, J¼148 Hz); 52.3 (tm, J¼142 Hz);
57.3 (tm, J¼150 Hz); 66.3 (tm, J¼152 Hz); 124.0 (dm, J¼
205 Hz); 124.8 (dm, J¼205 Hz); 139.9 (sm, C-2); 173.0
(sm, CO); 180.2 (sm, CS). HRMS, m/z: 369.5473 found
(Calcd for C18H33N4O2S, Cþ requires: 369.5460).
1
yellowish oil. The thioureido ester 8 was controlled by H
and 13C NMR spectroscopy.
4.4.1. 1-{2-[3-(1-Benzyl-3-methyl-thioureido)-propionyl-
oxy]-ethyl}-3-methyl-imidazolium hexafluorophosphate
1
(8a). Yield¼94%. H NMR (acetone d 6, 300 MHz) d 2.79
(t, 2H, J¼7.2 Hz); 3.03 (d, 3H, J¼3.1 Hz); 3.90 (t, 2H, J¼
7.3 Hz); 4.01 (s, 3H); 4.46 (t, 2H; J¼4.8 Hz); 4.62 (t, 2H;
J¼4.8 Hz); 5.05 (s, 2H); 7.25–7.37 (m, 5H); 7.65 (d, 1H,
J¼1.7 Hz); 7.75 (d, 1H, J¼1.7 Hz), 9.40 (s, 1H). 13C NMR
(acetone d 6, 75 MHz) d 32.5 (t, J¼113 Hz); 33.3 (qm,
J¼140 Hz); 36.8 (q, J¼145 Hz); 46.5 (tm, J¼138 Hz); 49.5
(t, J¼146 Hz); 54.2 (tm, J¼150 Hz); 63.3 (tm; J¼153 Hz);
123.9 (dm, J¼210 Hz); 124.8 (dm, J¼205 Hz); 127.9 (dm,
J¼158 Hz); 129.3 (dd, J¼160, 7.1 Hz); 138.2 (dm, J¼
220 Hz); 138.5 (sm, Ar); 172 (sm, CO); 185 (Sm; CS).
HRMS, m/z: 389.2016 found (Calcd for C20H29N4O2S, Cþ
requires: 389.2011).
4.4.5. 1-{2-[3-(1-Benzyl-3-methyl-thioureido)-propionyl-
oxy]-ethyl}-3-methyl-imidazolium tetrafluoroborate
1
(8e). Yield¼94%. H NMR (acetone d 6, 300 MHz) d 2.79
(t, 2H, J¼7.2 Hz); 3.03 (d, 3H, J¼3.1 Hz); 3.90 (t, 2H, J¼
7.3 Hz); 4.01 (s, 3H); 4.46 (t, 2H; J¼4.8 Hz); 4.62 (t, 2H;
J¼4.8 Hz); 5.05 (s, 2H); 7.25–7.37 (m, 5H); 7.65 (d, 1H,
J¼1.7 Hz); 7.75 (d, 1H, J¼1.7 Hz), 9.40 (s, 1H). 13C NMR
(acetone d 6, 75 MHz) d 32.5 (t, J¼113 Hz); 33.3 (qm,
J¼140 Hz); 36.8 (q, J¼145 Hz); 46.5 (tm, J¼138 Hz); 49.5
(t, J¼146 Hz); 54.2 (tm, J¼150 Hz); 63.3 (tm; J¼153 Hz);
123.9 (dm, J¼210 Hz); 124.8 (dm, J¼205 Hz); 127.9 (dm,
J¼158 Hz); 129.3 (dd, J¼160, 7.1 Hz); 138.2 (dm, J¼
220 Hz); 138.5 (sm, Ar); 172.0 (sm, CO); 185 (sm, CS).
HRMS, m/z: 389.2016 found (Calcd for C20H29N4O2S, Cþ
requires: 389.2011).
4.4.2. 1-{2-[3-Isobutyl-3-methyl-thioureido)-propionyl-
oxy]-ethyl}-3-methyl-imidazolium hexafluorophosphate
1
(8b). Yield¼96%. H NMR (acetone d 6, 300 MHz) d 0.89
(d, 6H, J¼6.7 Hz); 1.76 (m, 1H, J¼6.7 Hz); 2.80 (t, 2H,
J¼7.2 Hz); 3.01 (d, 3H, J¼7.1 Hz); 3.44 (d, 2H, J¼7.7 Hz),
4.02 (t, 2H, J¼7.5 Hz); 4.06 (s, 3H); 4.46 (t, 2H, J¼4.8 Hz);
4.68 (t, 2H, J¼4.5 Hz); 7.71 (d, 1H, J¼2.2 Hz); 7.80 (d, 1H,
J¼1.6 Hz); 9.07 (s, 1H). 13C NMR (acetone d 6, 75 MHz) d
20.2 (qm, J¼125 Hz); 27.2 (dm, J¼125 Hz); 32.5 (t, J¼
130 Hz); 36.8 (q, J¼144 Hz); 48.7 (t, J¼138 Hz); 49.5 (t,
J¼147 Hz); 60.9 (t, J¼130 Hz); 63.2 (t, J¼151 Hz); 124.0
(dm, J¼203 Hz); 124.8 (dm, J¼204 Hz); 138.2 (dm, J¼
220 Hz); 172.0 (m, CO); 183 (m, CS). HRMS, m/z:
327.1865 found (Calcd for C15H27N4O2S, Cþ requires:
327.1855).
4.4.6. 1-{2-[3-(1-Isobutyl-3-methyl-thioureido)-propionyl-
oxy]-ethyl}-3-methyl-imidazolium tetrafluoroborate
1
(8f). Yield¼96%. H NMR (acetone d 6, 300 MHz) d 0.89
(d, 6H, J¼6.7 Hz); 1.76 (m, 1H, J¼6.7 Hz); 2.80 (t, 2H,
J¼7.2 Hz); 3.01 (d, 3H, J¼7.1 Hz); 3.44 (d, 2H, J¼7.7 Hz),
4.02 (t, 2H, J¼7.5 Hz); 4.06 (s, 3H); 4.46 (t, 2H, J¼4.8 Hz);
4.68 (t, 2H, J¼4.5 Hz); 7.71 (d, 1H, J¼2.2 Hz); 7.80 (d, 1H,
J¼1.6 Hz); 9.07 (s, 1H). 13C NMR (acetone d 6, 75 MHz) d
20.2 (qm, J¼125 Hz); 27.2 (dm, J¼125 Hz); 32.5 (t, J¼
130 Hz); 36.8 (q, J¼144 Hz); 48.7 (t, J¼138 Hz); 49.5 (t,
J¼147 Hz); 60.9 (t, J¼130 Hz); 63.2 (t, J¼151 Hz); 124.0
(dm, J¼203 Hz); 124.8 (dm, J¼204 Hz); 138.2 (dm, J¼
220 Hz); 172.0 (m, CO); 183.0 (m, CS). HRMS, m/z:
327.1865 found (Calcd for C15H27N4O2S, Cþ requires:
327.1855).
4.4.3. 3-Methyl-1-{2-[3-(3-propyl-1-propyl-thioureido)-
propionyloxy]-ethyl}-imidazolium hexafluorophosphate
1
(8c). Yield¼98%. H NMR (acetone d 6, 300 MHz) d 0.85
(t, 3H, J¼7.4 Hz); 1.62 (m, 2H, J¼7.9 Hz); 2.79 (t, 2H,
J¼7.4 Hz); 2.99 (d, 3H, J¼3.2 Hz); 3.53 (t, 2H, J¼7.9 Hz);
3.96 (t, 2H, J¼7.9 Hz); 4.06 (s, 3H); 4.50 (t, 2H, J¼5.2 Hz);
4.66 (t, 2H, J¼4.4 Hz); 7.71 (d, 1H, J¼1.6 Hz); 7.81 (d, 1H,
J¼1.7 Hz); 9.09 (s, 1H). 13C NMR (acetone d 6, 75 MHz) d
12.0 (q, J¼130 Hz); 21.2 (tm, J¼128 Hz); 32.8 (q, J¼
140 Hz); 33.0 (tm, J¼130 Hz); 36.8 (q, J¼150 Hz); 47.9
(tm, J¼140 Hz); 49.5 (t, J¼148 Hz); 52.3 (tm, J¼142 Hz);
63.3 (tm, J¼153 Hz); 124.0 (dm, J¼205 Hz); 124.8 (dm,
J¼205 Hz); 139.9 (sm, 1H); 173.0 (sm, CO), 183.0 (sm,
CS). HRMS, m/z: 313.2007 found (Calcd for C14H25N4O2S,
Cþ requires: 313.2011).
4.4.7. 3-Methyl-1-{2-[3-(3-methyl-1-propyl-thioureido)-
propionyloxy]-ethyl}-imidazolium tetrafluoroborate
1
(8g). Yield¼96%. H NMR (acetone d 6, 300 MHz) d 0.85
(t, 3H, J¼7.4 Hz); 1.62 (m, 2H, J¼7.9 Hz); 2.79 (t, 2H,
J¼7.4 Hz); 2.99 (d, 3H, J¼3.2 Hz); 3.53 (t, 2H, J¼7.9 Hz);
3.96 (t, 2H, J¼7.9 Hz); 4.06 (s, 3H); 4.50 (t, 2H, J¼5.2 Hz);
4.66 (t, 2H, J¼4.4 Hz); 7.71 (d, 1H, J¼1.6 Hz); 7.81 (d, 1H,
J¼1.7 Hz); 9.09 (s, 1H). 13C NMR (acetone d 6, 75 MHz) d
12.0 (q, J¼130 Hz); 21.2 (tm, J¼128 Hz); 32.8 (q, J¼
140 Hz); 33.0 (tm, J¼130 Hz); 36.8 (q, J¼150 Hz); 47.9
(tm, J¼140 Hz); 49.5 (t, J¼148 Hz); 52.3 (tm, J¼142 Hz);
63.3 (tm, J¼153 Hz); 124.0 (dm, J¼205 Hz); 124.8 (dm,
J¼205 Hz); 139.9 (sm, 1H); 173.0 (sm, CO), 183.0 (sm,
CS). HRMS, m/z: 313.2007 found (Calcd for C14H25N4O2S,
4.4.4. 1-{2-[3-(3-Butyl-1-isobutyl-thioureido)-propionyl-
oxy]-ethyl}-3-methyl-imidazolium hexafluorophosphate
C
þ requires: 313.2011).
1
(8d). Yield¼90%. H NMR (acetone d 6, 300 MHz) d 0.75
(t, 3H, J¼7.3 Hz); 0.80 (d, 6H, J¼6.7 Hz); 1.22 (m, 2H, J¼
7.7 Hz); 1.45 (m, 2H, J¼7.3 Hz); 1.45 (m, 1H, J¼6.9 Hz);
2.07 (t, 2H, J¼6.6 Hz); 2.71 (t, 2H, J¼6.8 Hz); 3.50 (d, 2H,
4.4.8. 1-{2-[3-(3-Butyl-1-isobutyl-thioureido)-propionyl-
oxy]-ethyl}-3-methyl-imidazolium tetrafluoroborate
1
(8h). Yield¼94%. H NMR (acetone d 6, 300 MHz) d 0.75

3752
H. Hakkou et al. / Tetrahedron 60 (2004) 3745–3753
(t, 3H, J¼7.3 Hz); 0.80 (d, 6H, J¼6.7 Hz); 1.22 (m, 2H, J¼
7.7 Hz); 1.45 (m, 2H, J¼7.3 Hz); 1.45 (m, 1H, J¼6.9 Hz);
2.07 (t, 2H, J¼6.6 Hz); 2.71 (t, 2H, J¼6.8 Hz); 3.50 (d, 2H,
J¼7.5 Hz); 3.52 (t, 2H, J¼7.4 Hz); 3.95 (s, 3H); 4.43 (t, 2H,
J¼5 Hz); 4.60 (t, 2H, J¼4.5 Hz); 7.71 (d, 1H, J¼1.6 Hz);
7.81 (d, 1H, J¼1.7 Hz); 9.09 (s, 1H). 13C NMR (acetone d 6,
75 MHz) d 13.95 (qm, J¼125 Hz); 18.9 (tm, J¼126 Hz);
19.9 (qm, J¼125 Hz); 26.9 (dm, J¼128 Hz); 30.6 (tm,
J¼125vHz); 31.4 (tm, J¼132 Hz); 36.8 (q, J¼150 Hz); 45.8
(tm, J¼139 Hz); 49.5 (t, J¼148 Hz); 52.3 (tm, J¼142 Hz);
57.3 (tm, J¼150 Hz); 66.3 (tm, J¼152 Hz); 124.0 (dm,
J¼205 Hz); 124.8 (dm, J¼205 Hz); 139.9 (sm, C-2); 173.0
(sm, CO); 180.2 (Sm, CS). HRMS, m/z: 369.5473 found
(Calcd for C18H33N4O2S, Cþ requires: 369.5460).
(d, 6H, J¼6.7 Hz); 1.33 (m, 2H, J¼7.7 Hz); 1.62 (m, 2H,
J¼7.3 Hz); 2.28 (m, 1H, J¼6.9 Hz); 2.75 (t, 2H, J¼6.6 Hz);
3.57 (t, 2H, J¼6.8 Hz); 3.82 (d, 2H, J¼7.5 Hz); 4.25 (t, 2H,
J¼6.1 Hz). 13C NMR (CDCl3, 75 MHz) d 13.8 (qm, J¼
1245 Hz); 19.9 (tm, J¼123 Hz); 20.2 (qm, J¼125 Hz); 26.9
(dm, J¼128 Hz); 30.0 (tm, J¼126 Hz); 31.4 (tm, J¼
133 Hz); 45.8 (tm, J¼139 Hz); 46.2 (tm, J¼136 Hz); 63.1
(tm, J¼139 Hz); 166.0 (sm, CO); 181.2 (sm, CS). HRMS,
m/z: 242.3082 found (Calcd for C12H22N2OS, Mþ requires:
242.3081).
4.5.4. 3-Methyl-1-propyl-2-thioxo tetrahydro pyrimidin-
4(1H)-one (9d). Yield¼83%. Rf¼0.5 with CHCl3 as eluent.
1H NMR (CDCl3, 300 MHz) d 0.98 (t, 3H, J¼7.4 Hz); 1.75
(m, 2H, J¼7.6 Hz); 2.78 (t, 2H, J¼6.8 Hz); 3.50 (s, 3H);
3.65 (t, 2H, J¼6.9 Hz); 3.95 (t, 2H, J¼7.7 Hz). 13C NMR
(CDCl3, 75 MHz) d 11.0 (qm, J¼126, 4 Hz); 20.0 (tm,
J¼124 Hz); 43.4 (tt, J¼133, 6.8 Hz); 34.0 (q, J¼142 Hz);
44.5 (tm, J¼143 Hz); 56.6 (tm, J¼139 Hz); 166.6 (sm, CO);
180.9 (sm, CS). HRMS, m/z: 186.0833 found (Calcd for
C8H14N2OS, Mþ requires: 186.0827).
4.5. Standard procedure for cleavage/cyclization of the
thio ureido esters 8 under solventless microwave
dielectric heating: preparation of 2-thioxo tetrahydro-
pyrimidin-4(1H)-ones 9(a-d)
A mixture of thioureido ester 8 (1 equiv.) and commercial
diethylamine (2 equiv.) was placed in a cylindrical quartz
reactor (B¼1.8 cm). Then the reactor was introduced into a
Synthewavew 402 Prolabo microwave oven. The liquid
mixture was stirred mechanically and was irradiated at
120 8C (20% power level, i.e., 60 W) for a reaction time
ranging from 15 to 45 min (see Table 4). After microwave
dielectric heating, the crude reaction mixture was allowed to
cool down at 25 8C and chloroform (5 mL) was added in the
cylindrical quartz reactor. The resulting solution was half
concentrated by rotary evaporation and the crude solution
was submitted to purification by flash chromatography
(column: B¼1 cm, H¼7 cm) on silica gel 60F-254 (Merck)
using CHCl3 or AcOEt as eluent. The desired fraction was
concentrated in vacuo and gave compound 8 as a yellowish
nearly pure oil. The pure products 9(a-d) were characterized
Acknowledgements
One of us (H.H.) thank the EEC for a research fellowship
(contrat N8 G5RD-CT 2001-00546). The authors thank also
Merck Eurolab Prolabo (Fr.) for providing the Synthewave
402w apparatus.
References and notes
1. (a) Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Applel, J. R.;
Doley, C. T.; Cuervo, J. H. Nature 1991, 345, 8436.
(b) Czarnik, A. W.; DeWitt, S. H. A practical guide to
combinatorial chemistry; American Chemical Society:
Washington, DC, 1997. (c) Senecci, P. Solid phase synthesis
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2. (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555.
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1
by H, 13C NMR and HRMS.
4.5.1. 3-Methyl-1-(phenylmethyl)-2-thioxo-tetrahydro
pyrimidin-4(1H)-one (9a). Yield¼85%. Rf¼0.4 with
1
CHCl3 as eluent. H NMR (CDCl3, 300 MHz) d 2.64 (t,
2H, J¼6.8 Hz); 3.48 (t, 2H, J¼6.8 Hz); 3.58 (s, 3H); 5.28 (s,
2H); 7.28–7.39 (m, 5H). 13C NMR (CDCl3, 75 MHz) d 31.3
(tm, J¼133 Hz); 34.8 (q, J¼142 Hz); 43.4 (t, J¼143 Hz);
58.3 (t, J¼141 Hz); 127.8 (dm, J¼160 Hz); 128.2 (dm, J¼
160 Hz); 129.0 (dd, J¼160, 5 Hz); 135.5 (sm, Ar); 167.0
(sm, CO); 182.5 (sm, CS). HRMS, m/z: 234.0821 found
(Calcd for C12H14N4OS, Mþ requires: 234.0824).
3. Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Comb. Chem. 2001,
3, 521.
4. Hobbs Dewitt, S.; Kiely, J. S.; Stankovic, C. J.; Schroeder,
M. C.; Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl. Acad.
Sci. U.S.A. 1993, 90, 6909.
4.5.2. 1-Isobutyl-3-methyl-2-thioxo tetrahydro pyrimi-
din-4(1H)-one (9b). Yield¼72%. Rf¼0.6 with CHCl3 as
5. Murphy, M. M.; Schullek, J. R.; Gordon, E. M.; Gallop, M. A.
J. Am. Chem. Soc. 1995, 117, 7029.
1
eluent. H NMR (CDCl3, 300 MHz) d 0.99 (d, 6H, J¼
6. Bendale, P. M.; Sun, C. M. J. Comb. Chem. 2002, 4, 359.
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Meyer, J. P.; Houghten, R. A. J. Org. Chem. 1998, 63, 8622.
6.7 Hz); 2.28 (m, 1H, J¼6.8 Hz); 2.75 (t, 2H, J¼6.8 Hz);
3.53 (s, 3H); 3.61 (t, 2H, J¼6.9 Hz); 3.81 (d, 2H, J¼7.5 Hz).
13C NMR (CDCl3, 75 MHz) d 20.2 (qm, J¼124 Hz); 27.0
(dm, J¼125 Hz); 31.4 (tt, J¼133, 3.4 Hz); 34.2 (q, J¼
142 Hz); 45.7 (tt, J¼142, 3.7 Hz); 63.0 (tm, J¼138 Hz);
167.0 (sm, CO); 182.0 (sm, CS). HRMS, m/z: 200.0983
found (Calcd for C9H16N2OS, Mþ requires: 200.0983).
´
8. Robert, G. F.; Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
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C. M. Comb. Chem. High Throughput Screen. 1999, 2, 299.
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2000, 3, 454.
4.5.3. 3-Butyl-1-isobutyl-2-thioxo tetrahydro pyrimidin-
4(1H)-one (9c). Yield¼67%. Rf¼0.5 with CHCl3 as eluent.
1H NMR (CDCl3, 300 MHz) d 0.92 (t, 3H, J¼7.3 Hz); 0.98
13. Larhed, M.; Hallberg, A. Drug Discov. Today 2001, 6, 406.

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¨
18. For reviews, see: (a) Lidstrom, P.; Tierney, J.; Wathey, B.;
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Diaz-Ortis, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem.
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(d) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
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Jacquault, P.; Mathe, D. Synthesis 1998, 1213. (e) Caddick, S.
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22. (a) Commarmot, R.; Didenot, R.; Gardais, J. F. Fr Demande
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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.
19. This work was presented at ‘XIIeme Conferences Europeennes
du Groupement des Pharmacochimistes de l’Arc Atlantique—
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