Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the preparation of new 3,4-dihydropyrimidine-2(1H)-ones bearing bioisostere group in N-3 position

Article abstract of DOI:10.1016/j.tet.2008.03.021

The ionic liquid phase organic synthesis (IoLiPOS) methodology has been used for the preparation of new 3,4-dihydropyrimidine-2(1H)-ones (DHPMs) bearing bioisostere group in N-3 position. For the 3,4-DHPMs substituted with various thiazole rings, the stra

Full text of DOI:10.1016/j.tet.2008.03.021

Tetrahedron 64 (2008) 5328–5335
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the
preparation of new 3,4-dihydropyrimidine-2(1H)-ones bearing bioisostere
group in N-3 position
,
Jean Christophe Legeaya, Jean Jacques Vanden Eynde b, Jean Pierre Bazureau a
*
a Universite´ de Rennes 1, Laboratoire Sciences Chimiques de Rennes, UMR CNRS 6226, Groupe Inge´nierie Chimique & Mole´cules pour le Vivant (ICMV),
ˆ
´ ´
Bat. 10A, Campus de Beaulieu, Avenue du General Leclerc, CS 74205, 35042 Rennes Cedex, France
b
´
´
´
´
Universite de Mons-Hainaut, Academie Universitaire Wallonie-Bruxelles, Faculte des Sciences, Departement de Chimie Organique, 20 Place du Parc, 7000 Mons, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The ionic liquid phase organic synthesis (IoLiPOS) methodology has been used for the preparation of new
3,4-dihydropyrimidine-2(1H)-ones (DHPMs) bearing bioisostere group in N-3 position. For the 3,4-
DHPMs substituted with various thiazole rings, the strategy involved a three-component Biginelli con-
densation in the second step with good yields (93–96%) from ILP bound acetoacetate, aromatic aldehyde
(93–97% yield), and N-methyl urea followed by N-3 alkylation with chloroacetonitrile on the ILP bound
3,4-DHPM. Quantitative thionation of the nitrile group grafted on the ILP bound 3,4-DHPM was realized
in MeOH with a 40–48% solution of ammonium sulfide and subsequent addition of a-bromoketone
produced the thiazole ring appended on the 3,4-DHPM core. After cleavage by transesterification, the
target compounds were obtained in good overall yields (47–50%). The efficiency of the IoLiPOS
methodology was also demonstrated by the preparation of new 3,4-DHPMs with a tetrazole ring in N-3
Received 29 November 2007
Received in revised form 14 February 2008
Accepted 7 March 2008
Available online 12 March 2008
Keywords:
Ionic liquid phase
3,4-Dihydropyrimidine-2(1H)-one
Bioisostere
Biginelli
Hantzsch
position in
5
steps (53–61% overall yield) via the ILP bound 3-cyanomethyl 3,4-DHPM as key
Thiazole
Tetrazole
intermediate.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the discovery of new leads or series, based on existing key ligands.
The thiazole heterocycle was used as pyrazole bioisostere in the CB1
Over the years, research interest in multi-functionalized 3,4-
dihydropyrimidine-2(1H)-ones (DHPMs), has surged rapidly, owing
to the pharmacological properties associated with many derivatives
of this privileged heterocyclic core. A number of recent publications
has emerged describing structural variations in N-3 functionalized
DHPMs as calcium channel modulators, which exhibit similar bi-
ological profiles to DHPs.1 Notably, N-3 functionalized 4-aryl-3,4-
dihydropyrimidine-2(1H)-ones exhibit a broad range of biological
effects2 and have recently appeared as, e.g., a1a adrenergic receptor
(SNAP 6552)3 and antihypertensive agents (SQ 32926).4 Due to the
fact that the aminopropyl 4-piperidinyl heterocycle attached to
DHPM moiety via a N-3 carboxamide linkage has proven to be
excellent template for the treatment of benign prostatic hyperpla-
sia,5 the investigation of new functionalized DHPMs with structural
diversity on N-3 position has been advocated. For the present work,
the amide function in N-3 position of the DHPM scaffold will be
replaced by thiazole and tetrazole rings as bioisostere groups.
Bioisostere replacement6 forms a rational medicinal approach for
receptor antagonist rimonabant7 (SR 14176A) and the tetrazole ring
was well known as efficient isosteric substitute8 for the carboxylic
group in biologically active molecules, because they both possess
comparable acidity and sizes.9 The tetrazole unit, however, has
proved to be superior in resisting metabolic degradation.
Modern drug discovery steadily relies on high-speed organic
synthesis and combinatorial chemistry techniques for the rapid
generation of compound libraries. In recent years, task-specific
ionic liquids (TSILs)10 and ionic liquid phases11 (ILPs)da subclass of
TSILs as alternative soluble supports for liquid phase organic syn-
thesis of small molecules12dare receiving growing attention due to
their tuneable features for various targeted chemical tasks and the
advantages as homogeneous supports. This concept was success-
fully used to a wide range of applications13 such as a b-lactam
library14 via multistep reactions, oligonucleotide,15 oligosaccha-
ride,16 and peptide17 synthesis to mention, but few recent exam-
ples. Undoubtedly, the IL-supported synthesis possesses the
advantages common to homogeneous solution-phase synthesis.
In this context, our aim in this study was to develop a novel ionic
liquid phase strategy toward new 3,4-dihydropyrimidine-2(1H)-
ones bearing in N-3 position a thiazole or a tetrazole ring as bio-
isosteric substitute. Herein, we present a full account of this study
* Corresponding author. Fax: þ33 (0) 2 23 23 63 74.
E-mail address: jean-pierre.bazureau@univ-rennes1.fr (J.P. Bazureau).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.021

J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
5329
X
N
O
i
ii
O
Me
Me
OH
, PF6
IL
IL
N
N
OH
IL
O
NH
Me
H2N NHMe
O
O
CO2t-Bu
O
O
O
X
Me
O
Me
1: [HOC2mim][PF6]
Ionic Liquid Phase
4 (X = Cl, Br)
5
2
3
6
X
N
Cl
N
Cl
O
O
O
iii
iv
v
vi
S
IL
O
IL
IL
S
N
CN
O
N
O
N
R
Cl CN
X
NH2
N
O
Me
O
Me
O
Me
N
Me
O
R
Me
Me
7
8
9
10
11
Cl
X
N
X
O
O
O
vii
viii
S
N
IL
N
MeO
Me
N
MeO
Me
N
O
N
NH
NH
N
N
N
N
N
Me
O
O
N
Me
N
Me
O
R
Me
12
13
14
Scheme 1. Preparation of N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones 12 and 14 using IoLiPOS methodology. Reagents and reaction conditions: (i) tert-butyl acetoacetate 2
(2.5 equiv), 170 ꢀC, mu, 150 W, 10 min. (ii) HCl (0.5 mol %), 4-halogenobenzaldehyde 4 (1 equiv), N-methylurea 5 (3 equiv), 100 ꢀC, 1 h. (iii) chloroacetonitrile 7 (2 equiv), NaH
(2 equiv), MeCN, 0 ꢀC, 18 h. (iv) (NH4)2S (4 equiv), MeOH, 25 ꢀC, 72 h. (v) halogenoketone 10 (1.01 equiv), DMF, 90 ꢀC, 16 h. (vi) MeONa (1 equiv), MeOH, reflux, 15 h. (vii) NaN3,
NH4Cl, DMF, 100 ꢀC, 24 h. (viii) MeONa (2 equiv), MeOH, reflux, 18 h, then 3 M HCl (pH¼2).
according to the ‘ionic liquid phase organic synthesis (IoLiPOS)’
methodology.
Table 1) of tert-butyl acetoacetate 2 with [HOC2mim][PF6] ILP 1
under solvent-free microwave irradiation18 after 10 min with
a stoichiometry of 1:2.5 of ILP 1/b-ketoester 2. The optimal reaction
mixture was 170 ꢀC, just below the boiling point of reagent 2 and
for safety reasons, a 6-min heating ramp was performed before the
temperature19 was maintained at the selected maximum value of
170 ꢀC (at 150 W in the SynthewaveÒ 402 reactor20). For the syn-
thesis of ILP bound 3,4-DHPM 6 in the second step, we have used
the one-pot three-component Biginelli21 formation. A mixture with
a stoichiometry of 1:1:3 of IL-phase 3/4-halogenobenzaldehyde 4/
N-methyl urea 5, respectively, and a catalytic amount of hydro-
chloric acid (0.5 mol %) was found to react completely without
solvent in the three-component Biginelli condensation22 at 100 ꢀC
for 1 h to produce the 3,4-DHPMs 6(a,b) (93–96% yield) grafted on
ionic liquid phases. The excess of N-methyl urea 5 could be re-
moved by simple washings with cold deionized water (1:10 w/v),
due to the low miscibility of the IPLs 6 in cold water.
2. Results and discussion
The overall strategy for the target N-3 functionalized 3,4-dihy-
dropyrimidine-2(1H)-ones bearing a thiazole or tetrazole ring is
outlined in Scheme 1.
In this context, we were interested in the preparation of 3,4-
DHPMs grafted on the ionic liquid phase (ILP) to introduce diversity
on N-3 position via the key intermediate 8. The nitrile group of the
scaffold 8 was expected to be a suitable precursor for the thiazole
Hantzsch synthesis. The 3,4-dihydropyrimidine-2(1H)-one 8 of
interest was assembled via a multicomponent reaction of an alde-
hyde, urea, and b-ketoester as shown in Figure 1. The construction
of an ester linkage between solid- or liquid phase supported hy-
droxyl functionality with carboxylic acid or ester is one of the most
common transformation in solid phase organic synthesis (SPOS) or
in liquid phase organic synthesis (LPOS). For this purpose, the
starting [HOC2mim][PF6] ILP 1 used was prepared according to two-
step process in large scale11 developed previously in our laboratory.
In the first step as shown in Scheme 1, the ionic liquid phase
bound b-ketoester 3 was obtained by transesterification (93% yield,
The third step is the preparation of the key intermediate 8 for
the elaboration of thiazole and tetrazole moieties. In order to obtain
the scaffold intermediate 8, the corresponding ionic liquid phase
bound 3,4-dihydropyrimidine-2(1H)-ones 6(a,b) were exposed to
a ClCH2CN 7/NaH/MeCN mixture, which effectively afforded at 0 ꢀC
the N-alkylated derivatives of ILP bound 3,4-DHPMs 8(a,b). The N-3
X
X
X
Hantzsch
thiazole
synthesis
Biginelli
O
O
O
Cl
"S"
O
synthesis
O
R1O
R1O
NH
S
R1O
N
Br
R4
NH2
O
C
N
R2
HN
R3
N
R2
O
R2
N
R3
O
N
R3
O
R4
X = Cl, Br
X = Cl, Br
Figure 1. Retrosynthetic strategy toward N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones bearing thiazole moiety as bioisostere group.

5330
J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
Table 1
Product
Starting compounds
X
R
Yielda (%)
Overall yieldb (%)
3
6a
6b
8a
8b
9
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
14a
14b
2
4a
4b
6a
6b
8a
9þ10a
9þ10b
9þ10c
9þ10d
11a
11b
11c
11d
8a
d
Cl
Br
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Br
d
90
96
93
97
93
96
85
65
88
84
73
71
71
70
79
71
92
96
d
d
86
84
84
78
80
68
52
71
68
50
37
50
47
66
55
61
53
d
d
d
d
C6H5
CH3
p-ClC6H4
p-MeOC6H4
C6H5
CH3
p-ClC6H4
p-MeOC6H4
d
8b
13a
13b
d
d
d
O
O
O
O
Br
Br
Br
O
O
Cl
Me
Br
Cl
MeO
Cl
4a
4b
10a
10b
10c
10d
a
Yield of isolated product.
Overall yield calculated from product 1.
b
alkylations23 are conveniently carried out in acetonitrile solution
using a two-fold excess of chloroacetonitrile 7 in the presence of
NaH24 (2 equiv) as a base. Further purification has been performed
by washings (1:10 w/v) successively with Et2O, deionized water,
and pentane, and finally were dried under high vacuum (10ꢁ2 Torr)
at 25 ꢀC for 4 h (8a: 97%, 8b: 93%). The scaffold intermediates 8(a,b)
were synthesized in three linear steps and 78–84% overall yield.
With the N-3 cyanomethyl 3,4-DHPM bound ILP 8 in hand, we
have examined the conversion of nitrile group to thioamide. Many
different methods have been reported in the literature for the
preparation of thioamides. In general, two approaches may be
adopted for the preparation of thioamides: (i) the thionation of the
corresponding amide with an electrophilic reagent, such as Law-
esson’s reagent25 or phosphorus pentasulfide26 or (ii) reaction with
a nucleophilic thionating reagent, by electrophilic activation of an
amide27 or more simply using the corresponding nitrile.28 The
latter conversion requires the use of toxic hydrogen sulfide with
a basic catalyst (Et3N, pyridine) and the alternative reagents
was encountered by reaction of 4 equiv of ammonium sulfide with
3,4-DHPM 8a (X¼Cl) at 20 ꢀC for 72 h. Pure thioamide bound ILP 9
was obtained at this stage in 96% yield after washings with
deionized water (1:10 w/v).
In step 5, our focus was the transformation of the thioamide
bound ILP 9 into thiazole derivative 11 by Hantzsch reaction.
Initially our studies started by the reaction of thioamide 9 and a-
bromoketone 10 using various solvents as EtOH,33 DMF,34 and
DME35 at various reaction temperature (70–110 ꢀC) in the pres-
ence of K2CO3. Among the reaction conditions evaluated, we
found that reaction of 9 with 1.01 equiv of a-halogenoketone 10
(X¼Br, Cl) in DMF (0.6 ml/mmol) at 90 ꢀC gave good thiazole
formation after 16 h. As it can be seen from inspection of the
data presented in Table 1, the thiazole 11(a–d) issued, re-
spectively, from bromoacetophenone 10a, chloroacetone 10b,
2-bromo-40-chloroacetophenone
10c,
2-bromo-40-methoxy-
acetophenone 10d were obtained in yields ranging from 65 to
88% after successive washings (deionized water, Et2O, pentane)
and drying under reduced pressure. It is worth noting that the
Hantzsch thiazole products 12 were estimated easily by 1H NMR
without detaching the material from the ionic liquid phase. In
the last step, the thiazole derivatives 12 appended to the 3,4-
DHPM moiety were released from the ILP 11 by treatment with
sodium methoxide (1 equiv) in refluxing MeOH for 15 h. Cleavage
by transesterification led to the starting ILP 1 and thiazole 12,
which could be easily separated by flash filtration36 on alumina
gel using AcOEt (Rf¼1.0) as eluent. 3,4-DHPMs 12(a–d) func-
tionalized with a thiazole ring were obtained in good yields (70–
73%) and the structure of the new DHPMs was ascertained by
conventional techniques (1H, 13C NMR) and the purity was con-
trolled by HRMS. The experiments demonstrate that the ILP
bound b-ketoester 3 afforded the target 3,4-DHPMs 12 in mod-
erate to good overall yields (37–50%) in five steps via Biginelli
and Hantzsch reactions.
(Dowex-SH,29 P4S11Na2 or sodium trimethylsilanethiolate31) re-
30
quire initial preparation. Ammonium sulfide in MeOH has emerged
as the less unpleasant-smelling source of hydrogen sulfide for the
synthesis of thioamides from nitrile32 with appreciable yields. On
the basis of this work, we have examined the use of ammonium
sulfide in MeOH under several reaction conditions for the trans-
formation of 8 into thioamide 9 (Table 2). The best result (entry 3)
Table 2
Reaction conditions used for thionation of 3,4-DHPM bound ILP 8
Entry
Reaction
temperature (ꢀC)
Reaction
time (h)
Ammonium
sulfide (equiv)
Yielda of 9 (%)
1
2
3
4
5
6
20
20
20
65
65
65
24
24
72
24
24
24
2
4
4
1
2
4
0
73
96
0
In order to establish the scope of the cyanomethyl chain
appended to the 3,4-DHPM moiety, we were interested in the
preparation of tetrazole derivatives using simple reaction condi-
tions. Previous approaches to the tetrazole ring formation
Decomposition
68b
a
Isolated yield.
Reaction conducted in a sealed tube.
b

J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
5331
presented some problems associated to (i) the need of highly toxic
trialkyltin azide37 in the conversion of arylnitrile intermediate to
tetrazole, (ii) the use of hazardous reagents,38 (iii) the use of ex-
pensive metallic species that generate dangerous metallic residues
not only harmful to human health but also to the environment.
Alternative approaches have been explored by the group of
Lukyanov39 under microwave irradiation from sterically hindered
nitriles. Our goal was to minimize the use of expensive and haz-
ardous metals and increase the overall efficiency of the tetrazole
synthesis. Initially, our studies started by reaction of nitrile in-
termediate 8 and various solvents (EtOH, DMF), various quantities
of sodium azide and ammonium chloride (Table 3) and different
reaction temperature according to known procedures.40
(Merck) or neutral alumina oxide gel 60 F254 (Merck). Visualization
was made with ultraviolet light (254 and 365 nm) or with a fluo-
rescence indicator. IR spectra were recorded on a BIORAD FTS 175C
spectrophotometer. 1H NMR spectra were recorded on BRUKER AC
300 P (300 MHz) spectrometer and 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, 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 MS/MS ZABSpec TOF
Micromass (EBE TOF geometry) at an ionizing potential of 8 eV for
the ILPs and on a VARIAN MAT 311 at an ionizing potential of 70 eV
´
Entries 3 and 5 show that the optimal reaction conditions in-
volved a mixture constituted of 2 equiv of NaN3 and NH4Cl in DMF
at 100 ꢀC that gave after 24 h the desired ILP bound tetrazole 13 in
good yields (13a: 79% and 13b: 71%). After purification by washings
with deionized water, the ILP bound tetrazole 13 was treated with
sodium methoxide (2 equiv) in refluxing MeOH for 24 h followed
by controlled acidification with a solution of 3 M HCl at room
temperature. Due to the low miscibility of the expected tetrazole 14
in the acidic crude reaction mixture (pH 2), filtration and purifi-
cation by washings (with cold deionized water) afforded the de-
sired tetrazole methyl ester 14 (92–96% yields). According to this
approach the compounds 14(a,b) were prepared in 5 steps with
good overall yields (14a: 61% and 14b: 53%) and the structure was
confirmed by conventional techniques (1H, 13C NMR, and HRMS).
for other compounds in the Centre Regional de Mesures Physiques
de l’Ouest (CRMPO, Rennes). Reactions under microwave irradia-
tions were realized in the SynthewaveÒ 402 apparatus (Merck
Eurolab, Div. Prolabo, France) in quartz open reactor vessel fitted
with a condenser The microwave instrument consists of a contin-
uous focused microwave power output from 0 to 300 W. All the
experiments were performed using stirring option. The target
temperature was reached with a ramp of 3 min and the chosen
microwave power stay constant to hold the mixture at this tem-
perature. The reaction temperature is monitored using calibrated
infrared sensor and the reaction time included the ramp period.
Acetonitrile was distilled over calcium chloride after standing
overnight and stored over molecular sieves (3 Å). Solvents were
evaporated with
a BUCHI rotary evaporator. All reagents
were purchased from Acros, Aldrich Chimie, and Fluka France, and
were used without further purification. The starting [HOC2-
mim][PF6] ionic liquid phase 111 was synthesized according to our
previous method.
3. Conclusion
In summary, we have developed a highly versatile and general
ionic liquid phase protocol for the synthesis of new functionalized
3,4-dihydropyrimidine-2(1H)-ones. This approach is particularly
attractive for the preparation of 3,4-DHPMs bearing a thiazole ring
as bioisostere group in N-3 position with good overall yields using
Biginelli and Hantzsch reactions. By applying this ‘ionic liquid
phase organic synthesis (IoLiPOS)’ methodology we were able to
extend this strategy to the synthesis of new 3,4-DHPMs with
a tetrazole ring in N-3 position in five steps via the 3-cyanomethyl
DHPM 8 as key intermediate. The further use of this scaffold in-
termediate 8 as a starting point of diversity is ongoing. We are
currently exploring the scope and the potential of the 3-cyano-
methyl 3,4-DHPM 8 grafted on the ionic liquid phase for the
preparation and biological screening of a wider library.
4.2. 1-[2-(Acetoacetyloxy) ethyl]-3-methyl-imidazolium
hexafluorophosphate (3)
In
a
cylindrical quartz reactor (B¼1.8 cm) was placed
a
mixture of 1-(2-hydroxyethyl)-3-methyl-imidazolium hexa-
fluorophosphate 1 (3.4 g, 13 mmol) and tert-butyl acetoacetate 2
(5.4 g, 33.8 mmol). The reactor was then introduced into a Synthe-
waveÒ 402 Prolabo microwave reactor. The stirred mixture was
irradiated (after a ramp of 6 min from 25 to 170 ꢀC) at 170 ꢀC
(power level: 50%, 150 W) for 10 min. After microwave dielectric
heating, the crude reaction mixture was allowed to cool down at
room temperature and acetone (10 ml) was added in the cylindrical
quartz reactor. The resulting solution was concentrated by rotary
evaporation under reduced pressure. The desired product 3 was
purified by washings with diethyl ether (2ꢂ25 ml) and AcOEt
(2ꢂ50 ml). The expected product 3 was further dried under high
vacuum (10ꢁ2 Torr) at 25 ꢀC for 3 h and was obtained as white
needles (mp¼85–87 ꢀC) in 90% yield. IR (KBr): 1712, 1746, 2977,
3168 cmꢁ1. 1H NMR ((CD3)2CO, TMS): d¼2.21 (s, 3H); 3.65 (s, 2H);
4. Experimental
4.1. General
Melting points were determined on a Kofler melting point ap-
paratus and were uncorrected. Thin layer chromatography (TLC)
was accomplished on 0.2-mm precoated plates of silica gel 60 F254
3
3
4.03 (s, 3H); 4.55 (t, 2H, JH,H¼5.1 Hz); 4.64 (t, 2H, JH,H¼5.1 Hz);
7.64 (s, 1H, H-4 or H-5); 7.72 (s, 1H, H-4 or H-5);, 8.87 (s, 1H, H-2).
13C NMR ((CD3)2CO, TMS): d¼30.16 (CH3); 36.51 (NCH3); 49.29
(CH2); 49.82 (CH2O); 63.32 (NCH2); 123.57–124.60 (C-4, C-5);
137.97 (C-2); 167.68 (OCO); 202.11 (CH3 CO). HRMS, m/z found:
211.1083 (calculated for C10H15N2O3, Cþ requires: 211.1082).
Table 3
Reaction conditions used for the synthesis of ILP bound tetrazole 13 after 24 h
Entry
X
NaN3
NH4Cl
(equiv)
Solvent
Reaction
temperature (ꢀC)
Yielda of 13
(%)
(equiv)
1
2
3
4
5
Cl
Cl
Cl
Cl
Br
2
2
2
1
2
2
2
2
1
2
db
130
79
100
100
100
0
0
79
93c
71
4.3. Standard procedure for the solventless three-component
synthesis of 3,4-DHPMs 6(a,b)
EtOH
DMF
DMF
DMF
A mixture of 1-[2-(acetoacetyloxy)ethyl]-3-imidazolium hexa-
fluorophosphate 3 (483.1 mg, 1.35 mmol), commercial 4-chlor-
obenzaldehyde 4a or 4-bromobenzaldehyde 4b (1.35 mmol,
1 equiv), commercial methylurea 5 (300.4 mg, 4.06 mmol, 3 equiv),
and 2 drops of concentrated HCl as catalyst was stirred vigorously
a
Isolated yields.
Without solvent.
b
c
Conversion of 8a into 13a estimated by 1H NMR until disappearance of the
starting product 8a.

5332
J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
at 100 ꢀC without solvent for 1 h. After cooling down to room
temperature, deionized water (10 ml) was added in the crude re-
action mixture. The desired insoluble 3,4-DHPM 6 was collected by
filtration and was purified by washing with diethyl ether (2ꢂ5 ml).
The expected 3,4-DHPM 6 was further dried under high vacuum
(10ꢁ2 Torr) at 25 ꢀC for 3 h. The pure product 6 was characterized by
1H, 13C NMR, and HRMS.
(CH2CN); 35.84 (NCH3); 47.94 (CH2N); 58.77 (C-40); 62.17 (CH2O);
102.08 (C-50); 116.29 (CN); 122.50–123.69 (C-4, C-5); 128.82–
128.85 (C-200, C-600, C-300, C-500); 133.05 (C-400); 136.81 (C-100); 138.72
(C-2); 151.30–152.05 (C-20; C-60); 164.33 (CO2CH2CH2). HRMS,
m/z found: 428.1485 (calculated for C21H23N5O335Cl, Cþ requires:
428.1489).
4.4.2. 1-[2-[4-(4-Bromophenyl)-3-(cyanomethyl)-1,6-dimethyl-
2-oxo-1,2,3,4-tetrahydropyrimidin-5-ylcarbonyloxy]ethyl]-
3-methylimidazolium hexafluorophosphate (8b)
4.3.1. 1-[2-[4-(4-Chlorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-ylcarbonyloxy]ethyl]-3-methylimidazolium
hexafluorophosphate (6a)
Yield¼93%, brown powder. 1H NMR (300 MHz, acetone-d6)
d¼2.56 (s, 3H, CH3); 3.29 (s, 3H, CONCH3); 4.05 (s, 3H, NCH3); 4.22
(d, 1H, J¼17.3 Hz, NCH2CN); 4.51 (d, 1H, J¼17.3 Hz, NCH2CN); 4.60–
4.71 (m, 4H, NCH2CH2O); 5.50 (s, 1H, H-40); 7.30 (d, 2H, J¼8.3 Hz, H-
200, H-600); 7.51 (d, 1H, J¼8.3 Hz, H-300, H-500); 7.67 (s, 1H, H-4 or H-5);
7.69 (s, 1H, H-4 or H-5); 9.07 (s, 1H, H-2). 13C NMR (75 MHz, ace-
tone-d6) d¼16.63 (CH3); 31.27 (CONCH3); 35.84 (CH2CN); 36.69
(NCH3); 49.38 (CH2N); 60.13 (C-40); 62.79 (CH2O); 103.07 (C-50);
116.47 (CN); 122.70 (C-400); 123.55–124.76 (C-4, C-5); 130.11 (C-200,
C-600); 132.72 (C-300, C-500); 137.54 (C-2); 140.15 (C-100); 152.44–
152.75 (C-20, C-60); 165.17 (CO2CH2CH2). HRMS, m/z found:
472.0988 (calculated for C21H23N5O739Br, Cþ requires: 472.0984).
Yield¼96%, white needles, mp¼170–172 ꢀC. 1H NMR ((CD3)2SO,
300 MHz) d¼2.46 (s, 3H, CH3); 3.08 (s, 3H, CONCH3); 3.79 (s, 3H,
NCH3); 4.42 (m, 4H, NCH2CH2O); 5.07 (d,1H, J¼3.8 Hz, H-40); 7.12 (d,
2H, J¼8.4 Hz, H-200, H-600); 7.36 (d, 1H, J¼8.4 Hz, H-300, H-500); 7.59 (s,
1H, H-4 or H-5); 7.63 (s, 1H, H-4 or H-5); 8.12 (d, 1H, J¼3.8 Hz, NH);
9.02 (s, 1H, H-2). 13C NMR ((CD3)2SO, 75 MHz) d¼16.14 (CH3); 29.84
(CONCH3); 35.78 (NCH3); 47.93 (CH2O); 51.53 (C-40); 61.73 (CH2N);
100.62 (C-50); 122.38–123.53 (C-4, C-5); 127.97 (C-200, C-600); 128.46
(C-300, C-500); 131.98 (C-400); 136.71 (C-2); 142.58 (C-100); 152.75–
152.80 (C-20, C-60); 164.97 (CO2CH2CH2). HRMS, m/z found:
389.1383 (calculated for C19H22N4O335Cl, Cþ requires: 389.1380).
4.3.2. 1-[2-[4-(4-Bromophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-ylcarbonyloxy]ethyl]-3-methylimidazolium
hexafluorophosphate (6b)
4.5. Preparation of 1-[2-[3-(2-amino-2-thioxoethyl)-4-
(4-chlorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-ylcarbonyloxy]ethyl]-3-
methylimidazolium hexafluorophosphate (9)
Yield¼93%, yellow needles, mp¼184–186 ꢀC. 1H NMR ((CD3)2SO,
300 MHz) d¼2.46 (s, 3H, CH3); 3.08 (s, 3H, CONCH3); 3.80 (s, 3H,
NCH3); 4.42 (m, 4H, NCH2CH2O); 5.05 (d, 1H, J¼3.7 Hz, H-40); 7.06
(d, 2H, J¼8.4 Hz, H-200, H-600); 7.49 (d,1H, J¼8.4 Hz, H-300, H-500); 7.59
(s, 1H, H-4 or H-5); 7.62 (s, 1H, H-4 or H-5); 8.10 (d, 1H, J¼3.8 Hz,
NH); 9.00 (s, 1H, H-2). 13C NMR ((CD3)2SO, 75 MHz) d¼16.16 (CH3);
29.85 (CONCH3); 35.82 (NCH3); 47.94 (CH2O); 51.58 (C-40); 61.75
(CH2N); 100.56 (C-50); 120.53 (C-400); 122.39–123.55 (C-4, C-5);
128.34 (C-200, C-600); 131.39 (C-300, C-500); 136.72 (C-2); 143.00
(C-100); 152.83–152.75 (C-20, C-60); 164.96 (CO2CH2CH2). HRMS,
m/z found: 433.0878 (calculated for C19H21N4O739Br, Cþ requires:
433.0875).
In a 50 ml round bottomed flask fitted with a reflux condenser,
the compound 1-[2-[4-(4-chlorophenyl)-3-(cyanomethyl)-1,6-di-
methyl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-ylcarbonyloxy]ethyl]
-3-methylimidazolium
hexafluorophosphate
8a
(3.13 mg,
0.55 mmol) was dissolved in methanol pa (40 ml) under vigorous
magnetic stirring. To this solution, an aqueous solution of 40–48%
ammonium sulfide (NH4)2S (300 ml, 2.2 mmol, 4 equiv) was added
and the resulting mixture was stirred at room temperature for 3
days. Excess of ammonium sulfide was eliminated under reduced
pressure (10ꢁ2 Torr) for 3 h and the crude residue was washed with
deionized water (2ꢂ50 ml). The desired insoluble compound 9 was
collected by filtration and was washed again with deionized water
(2ꢂ10 ml). The expected thioamide 9 was further dried under high
vacuum (10ꢁ2 Torr) at 25 ꢀC for 4 h. Yield¼96%, brown foam. 1H
NMR (300 MHz, DMSO-d6) d¼2.44 (s, 3H, CH3); 3.16 (s, 3H,
CONCH3); 3.56 (d, 1H, J¼17 Hz, NCH2CS); 3.85 (s, 3H, NCH3);
4.31–4.51 (m, 4H, NCH2CH2O); 4.54 (d, 1H, J¼17 Hz, NCH2CS);
5.18 (s, 1H, H-40); 7.16 (d, 2H, J¼8.4 Hz, H-200, H-600); 7.38 (d, 2H,
J¼8.3 Hz, H-300, H-500); 7.69 (br s, 2H, H-4, H-5); 9.06 (s, 1H, H-2);
9.17 (br s, 1H, NH2); 9.75 (br s, 1H, NH2). 13C NMR (75 MHz,
DMSO-d6) d¼16.18 (CH3); 30.85 (CONCH3); 35.85 (NCH3); 47.81
(CH2N); 54.96 (NCH2CS); 57.76 (C-40); 61.78 (CH2O); 101.45 (C-
50); 122.69–123.64 (C-4, C-5); 128.37–128.65 (C-200, C-600, C-300, C-
500); 132.49 (C-400); 136.70 (C-100); 139.73 (C-2); 151.66–152.49
(C-20, C-60); 164.37 (CO2CH2CH2); 201.52 (C]S). HRMS, m/z
found: 462.1364 (calculated for C21H25N5O335ClS, Cþ requires:
462.1367).
4.4. Typical procedure for the preparation of compounds
8(a,b) by N-3 alkylation of compounds 7(a,b)
In a 100 ml two-necked round bottomed flask, provided with
a magnetic stirrer and reflux condenser, the compound 6a or 6b
(7.5 mmol) was dispersed in dry acetonitrile (30 ml) at 0 ꢀC. To this
mixture, sodium hydride (600 mg, 15 mmol, 60% dispersion in
mineral oil) was added portionwise under nitrogen and the re-
action mixture was stirred for 5 min. After which chloroacetonitrile
7 (970 ml, 1134.06 mg, 15.02 mmol) was added dropwise at 0 ꢀC
over 20 min. The reaction mixture was stirred at 0 ꢀC for 10 min
then at 25 ꢀC over a period of 18 h. After elimination of solvent in
a rotary evaporator under reduced pressure, the crude reaction
mixture was washed successively with Et2O (2ꢂ25 ml), deionized
water (2ꢂ25 ml), and pentane (2ꢂ25 ml). The desired product 8
was further dried under high vacuum (10ꢁ2 Torr) at 25 ꢀC for 4 h.
The product 7 was characterized by 1H, 13C NMR, and HRMS.
4.6. Standard procedure for the synthesis of compounds
11(a–d) functionalized with a thiazole group
4.4.1. 1-[2-[4-(4-Chlorophenyl)-3-(cyanomethyl)-1,6-dimethyl-
2-oxo-1,2,3,4-tetrahydropyrimidin-5-ylcarbonyloxy]ethyl]-
3-methylimidazolium hexafluorophosphate (8a)
In a 50 ml round bottomed flask, provided with a magnetic
stirrer and reflux condenser,1-[2-[3-(2-amino-2-thioxoethyl)-4-(4-
chlorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-
ylcarbonyloxy]ethyl]-3-methylimidazolium hexafluorophosphate
9 (316 mg, 0.52 mmol) and bromoacetophenone 10a (103.5 mg,
0.52 mmol) or chloroacetone 10b (55.76 mg, 48 ml, 0.52 mmol) or
2-bromo-40-chloroacetophenone 10c (120 mg, 0.52 mmol) or 2-
Yield¼97%, brown powder. 1H NMR (300 MHz, DMSO-d6)
d¼2.44 (s, 3H, CH3); 3.20 (s, 3H, CONCH3); 3.84 (s, 3H, NCH3); 4.32–
4.42 (m, 6H, NCH2CH2O, CH2CN); 5.34 (s, 1H, H-40); 7.22 (d, 2H,
J¼8.3 Hz, H-200, H-600); 7.39 (d, 1H, J¼8.3 Hz, H-300, H-500); 7.67 (s, 1H,
H-4 or H-5); 7.69 (s, 1H, H-4, H-5); 9.58 (s, 1H, H-2). 13C NMR
(75 MHz, DMSO-d6) d¼16.17 (CH3); 30.82 (CONCH3); 35.47

J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
5333
bromo-40-methoxyacetophenone 10d (119 mg, 0.52 mmol) were
4.6.4. 1-[2-[4-(4-Chlorophenyl)-1,6-dimethyl-3-[(4-(4-methoxy-
phenyl)-1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydro-
pyrimidin-5-ylcarbonyloxy]ethyl]-3-methylimidazolium
hexafluorophosphate (11d)
dispersed in dry dimethylformamide (0.5 ml). The reaction mixture
was heated at 90 ꢀC for 16 h under vigorous magnetic stirring, then
cooled down to room temperature. The reaction mixture was suc-
cessively washed with deionized water (2ꢂ5 ml), Et2O (2ꢂ5 ml),
and pentane (2ꢂ5 ml). The crude residue was dried under high
vacuum (10ꢁ2 Torr) at 25 ꢀC for 4 h. The pure product 11 was
characterized by 1H, 13C NMR, and HRMS.
Yield¼84%, brown foam. 1H NMR (300 MHz, acetone-d6) d¼2.56
(s, 3H, CH3); 3.31 (s, 3H, CONCH3); 3.84 (s, 3H, NCH3); 3.95 (s, 3H,
OCH3); 4.48 (d, 1H, J¼16 Hz, NCH2C-2%); 4.54–4.65 (m, 4H,
NCH2CH2O); 5.20 (d, 1H, J¼16 Hz, NCH2C-2%); 5.59 (s, 1H, H-40);
7.00 (d, 2H, J¼8.8 Hz, H-3&, H-5&); 7.32 (br s, 4H, H-200, H-600, H-300,
H-500); 7.54 (br s, 1H, H-4 or H-5); 7.58 (sl, 1H, H-4 or H-5); 7.68 (s,
4.6.1. 1-[2-[4-(4-Chlorophenyl)-1,6-dimethyl-3-[(4-phenyl-
1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidin-
5-ylcarbonyloxy]ethyl]-3-methylimidazolium hexafluoro-
phosphate (11a)
1H, H-5%); 7.90 (d, 2H, J¼8.8 Hz, H-2&, H-6&); 9.02 (s, 1H, H-2). 13
C
NMR (75 MHz, acetone-d6) d¼16.75 (CH3); 31.44 (CONCH3);
36.62 (NCH3); 48.45 (NCH2CS); 49.38 (CH2N); 55.60 (OCH3); 59.17
(C-40); 62.83 (CH2O); 102.98 (C-50); 112.90 (C-5%); 114.83 (C-5&, C-
3&); 123.52–124.56 (C-4, C-5); 128.04 (C-1&); 128.29 (C-6&, C-
2&); 129.51–129.73 (C-200, C-600, C-300, C-500); 134.01 (C-400); 137.56
(C-2); 140.71 (C-100); 152.79–153.54 (C- 20, C-60); 155.49 (C-4%);
160.54 (C-4&); 165.40 (CO2CH2CH2); 167.65 (C-2%). HRMS, m/z
Yield¼85%, brown foam. 1H NMR (300 MHz, acetone-d6) d¼2.56
(s, 3H, CH3); 3.31 (s, 3H, CONCH3); 3.95 (s, 3H, NCH3); 4.48–4.54 (m,
5H, NCH2CH2O, NCH2C-2%); 5.20 (d, 1H, J¼16 Hz, NCH2C-2%); 5.59
(s, 1H, H-40); 7.32–7.47 (m, 7H, H-200, H-600, H-300, H-500, H-4&, H-3&,
H-5&); 7.55 (br s,1H, H-4 or H-5); 7.57 (br s,1H, H-4 or H-5); 7.84 (s,
1H, H-5%); 7.96 (d, 2H, J¼7.2 Hz, H-2&, H-6&); 8.95 (s, 1H, H-2). 13
C
found: 592.1790 (calculated for
592.1785).
C
30H31N5O345ClS, Cþ requires:
NMR (75 MHz, acetone-d6) d¼16.74 (CH3); 31.43 (CONCH3); 36.58
(NCH3); 48.54 (NCH2C-2%); 49.37 (CH2N); 59.29 (C-40); 61.75
(CH2O); 102.98 (C-50); 114.93 (C-5%); 123.49–124.54 (C-4, C-5);
126.20 (C-2&, C-6&); 128.09–129.49–129.51–129.73 (C-200, C-600, C-
300, C-500, C-5&, C-6&, C-4&); 134.02 (C-1&); 135.18 (C-400); 137.43
(C-2); 140.68 (C-100); 152.73–153.54 (C-20, C-60); 155.50 (C-4%);
165.38 (CO2CH2CH2); 167.87 (C-2%). HRMS, m/z found: 562.1683
(calculated for C29H29N5O335ClS, Cþ requires: 562.1680).
4.7. Standard procedure for the preparation of compounds
12(a–c) by transesterification of ionic liquid phase bound
3,4-DHPMs 11(a–c)
To a solution of ionic liquid phase bound 3,4-DHPM 11
(740 mmol) in anhydrous methanol (15 ml), in a 50 ml round bot-
tomed flask fitted with a reflux condenser, was added commercial
sodium methoxide (40 mg, 740 mmol) in one portion under ni-
trogen. After vigorous stirring at 78 ꢀC for 18 h, the crude reaction
mixture was half concentrated in vacuo. Then, the resulting re-
action mixture was submitted to purification by flash chromatog-
raphy (column: B¼1 cm, H¼4 cm) on neutral alumina oxide 90 gel
(Merck) using AcOEt as eluent. The solvent of the desired fraction
(Rf¼0.9) was eliminated by rotary evaporation with reduced pres-
sure and the crude reaction mixture was further dried at 25 ꢀC for
3 h under high vacuum (10ꢁ2 Torr), which gave the expected
product 12. The pure product 12 was characterized by 1H, 13C NMR,
and HRMS.
4.6.2. 1-[2-[4-(4-Chlorophenyl)-1,6-dimethyl-3-[(4-methyl-
1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidin-
5-ylcarbonyloxy]ethyl]-3-methylimidazolium hexafluoro-
phosphate (11b)
Yield¼65%, brown foam. 1H NMR (300 MHz, acetone-d6) d¼2.34
(s, 3H, C-4%CH3); 2.55 (s, 3H, CH3); 3.29 (s, 3H, CONCH3); 4.04 (s,
3H, NCH3); 4.36 (d, 1H, J¼16.8 Hz, NCH2C-2%); 4.48–4.67 (m, 4H,
NCH2CH2O); 5.06 (d, 1H, J¼16 Hz, NCH2C-2%); 5.47 (s, 1H, H-40);
7.06 (s, 1H, H-5%); 7.29 (m, 4H, H-200, H-600, H-300, H-500); 7.61 (sl, 1H,
H-4 or H-5); 7.69 (br s, 1H, H-4 or H-5); 8.97 (s, 1H, H-2). 13C NMR
(75 MHz, acetone-d6) d¼16.70–16.92 (CH3, CH3C-4%); 31.39
(CONCH3); 36.66 (NCH3); 48.16 (NCH2C-2%); 49.44 (CH2N); 59.17
(C-40); 62.69 (CH2O); 102.91 (C-50); 115.34 (C-5%); 123.59–124.69
(C-4, C-5); 129.44–129.63 (C-200, C-600, C-300, C-500); 133.96 (C-
400); 137.51 (C-2); 140.71 (C-100); 152.69–153.10–153.47 (C-20,
C-60, C-4%); 165.32 (CO2CH2CH2); 166.75 (C-2%). HRMS, m/z
found: 500.1531 (calculated for C24H27N5O335ClS, Cþ requires:
500.1523).
4.7.1. Methyl 4-(4-chlorophenyl)-1,6-dimethyl-3-[(4-phenyl-
1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (12a)
Yield¼73%, white needles, mp¼220–222 ꢀC. IR (KBr): 1277,
1490, 1669, 1707, 2950, 3010, 3277 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d¼2.56 (s, 3H, CH3); 3.32 (s, 3H, CONCH3); 3.60 (s, 3H, OCH3); 4.43
(d, 1H, J¼16 Hz, NCH2C-200); 5.26 (d, 1H, J¼15.9 Hz, NCH2C-200); 5.65
(s, 1H, H-4); 7.29–7.47 (m, 7H, H-20, H-60, H-30, H-50, H-4%, H-3%, H-
5%); 7.82 (s, 1H, H-500); 8.00 (d, 2H, J¼7.2 Hz, H-2%, H-6%). 13C NMR
(75 MHz, CDCl3) d¼16.45 (CH3); 31.11 (CONCH3); 47.33 (NCH2C-200);
51.18 (OCH3); 58.07 (C-4); 103.81 (C-5); 113.51 (C-500); 126.11 (C-2%,
C-6%); 127.92–128.16–128.52–128.64 (C-20, C-60, C-30, C-50, C-5%, C-
6%, C-4%); 133.62 (C-1%); 134.09 (C-40); 139.01 (C-10); 149.33 (C-6);
153.27 (C-2); 155.07 (C-400); 165.70 (CO2CH3); 166.15 (C-200). HRMS,
m/z found: 293.0703 (calculated for C14H14N2O335Cl, [MꢁC10H8NS]þ
requires: 293.0693).
4.6.3. 1-[2-[4-(4-Chlorophenyl)-1,6-dimethyl-3-[(4-(4-chloro-
phenyl)-1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydro-
pyrimidin-5-ylcarbonyloxy]ethyl]-3-methylimidazolium
hexafluorophosphate (11c)
Yield¼88%, brown foam. 1H NMR (300 MHz, acetone-d6) d¼2.57
(s, 3H, CH3); 3.31 (s, 3H, CONCH3); 3.98 (s, 3H, NCH3); 4.53–4.67 (m,
5H, NCH2CH2O, NCH2C-2%); 5.15 (d, 1H, J¼16.0 Hz, NCH2C-2%); 5.61
(s, 1H, H-40); 7.31 (m, 4H, H-200, H-600, H-300, H-500); 7.46 (d, 2H,
J¼8.5 Hz, H-3&, H-5&); 7.57 (sl, 1H, H-4 or H-5); 7.62 (sl, 1H, H-4 or
H-5); 7.89 (s, 1H, H-5%); 7.96 (d, 2H, J¼8.5 Hz, H-2&, H-6&); 9.13 (s,
1H, H-2). 13C NMR (75 MHz, acetone-d6) d¼16.76 (CH3); 31.44
(CONCH3); 36.65 (NCH3); 48.74 (NCH2C-2%); 49.43 (CH2N); 59.52
(C-40); 62.80 (CH2O); 103.03 (C-50); 115.57 (C-5%); 123.57–124.61
(C-4, C-5); 128.54 (C-2&, C-6&); 129.48 (C-5&, C-3&); 129.57–
129.76 (C-200, C-600, C-300, C-500); 133.92–133.97–134.02 (C-1&, C-400,
C-4&); 137.55 (C-2); 140.79 (C-100); 152.72–155.54 (C-20, C-60);
154.17 (C-4%); 165.42 (CO2CH2CH2); 168.30 (C-2%). HRMS, m/z
found: 596.1299 (calculated for C29H28N5O335Cl2S, Cþ requires:
596.1290).
4.7.2. Methyl 4-(4-chlorophenyl)-1,6-dimethyl-3-[(4-methyl-
1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (12b)
Yield¼71%, brown foam. IR (KBr): 1210, 1457, 1674, 1705, 2853,
2952, 3274 cmꢁ1. 1H NMR (300 MHz, acetone-d6) d¼2.33 (s, 3H, C-
400CH3); 2.55 (s, 3H, CH3); 3.30 (s, 3H, CONCH3); 3.60 (s, 3H, OCH3);
4.30 (d, 1H, J¼16 Hz, NCH2C-200); 5.14 (d, 1H, J¼16 Hz, NCH2C-200);
5.50 (s, 1H, H-4); 7.03 (s, 1H, H-500); 7.32 (br s, 4H, H-20, H-60, H-30,
H-50). 13C NMR (75 MHz, acetone-d6) d¼16.63–16.95 (CH3, CH3C-

5334
J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
400); 31.32 (CONCH3); 47.98 (NCH2C-200); 51.45 (OCH3); 59.21 (C-4);
104.15 (C-5); 115.19 (C-500); 129.43–129.67 (C-20, C-60, C-30, C-50);
133.94 (C-40); 141.11 (C-10); 150.99 (C-6); 153.23–153.77 (C-2;
C-400); 166.40 (CO2CH3); 166.82 (C-200). HRMS, m/z found:
293.0703 (calculated for C14H14N2O335Cl, [MꢁC10H8NS]þ requires:
293.0693).
4.8.1. 1-[2-[4-(4-Chlorophenyl)-1,6-dimethyl-2-oxo-3-
(2H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydropyrimidin-
5-ylcarbonyloxy]ethyl]-3-methylimidazolium hexa-
fluorophosphate (13a)
Yield¼79%, brown foam. 1H NMR (300 MHz, DMSO-d6) d¼2.42
(s, 3H, CH3); 3.18 (s, 3H, CONCH3); 3.92 (s, 3H, NCH3); 4.10 (d, 1H,
J¼15 Hz, NCH2C-5%); 4.25–4.43 (m, 4H, NCH2CH2O); 5.14 (d, 1H,
J¼15 Hz, NCH2C-5%); 5.38 (s, 1H, H-40); 7.17 (d, 2H, J¼8.3 Hz, H-200,
H-600); 7.38 (d, 1H, J¼8.3 Hz, H-300, H-500); 7.69 (s, 1H, H-4 or H-5);
7.71 (s, 1H, H-4 or H-5); 9.11 (s, 1H, H-2). 13C NMR (75 MHz, DMSO-
d6) d¼16.10 (CH3); 30.89 (CONCH3); 35.88 (NCH3); 38.66 (NCH2C-
5%); 48.01 (CH2N); 56.38 (C-40); 61.97 (CH2O); 101.52 (C-50);
122.47–123.88 (C-4, C-5); 128.66–128.74 (C-200, C-600, C-300, C-500);
132.63 (C-400); 136.86 (C-100); 139.35 (C-2); 151.58–152.41 (C-20, C-
60); 154.68 (C-5%); 164.37 (CO2CH2CH2). 31P NMR (121 MHz, DMSO-
d6) d¼ꢁ144.07 (hept, JP–F¼711 Hz, PFꢁ6 ). HRMS, m/z found: 493.1477
(calculated for C21H23N8O335ClNa, [CꢁHþNa]þ requires: 493.1479),
found: 509.1216 (calculated for C21H23N3O335ClK, [CꢁHþK]þ re-
quires: 509.1219).
4.7.3. Methyl 4-(4-chlorophenyl)-1,6-dimethyl-3-[(4-(4-chloro-
phenyl)-1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydro-
pyrimidin-5-carboxylate (12c)
Yield¼71%, brown foam. IR (KBr): 1277, 1490, 1669, 1705, 2948,
3097, 3301 cmꢁ1
.
1H NMR (300 MHz, acetone-d6) d¼2.56 (s, 3H,
CH3); 3.32 (s, 3H, CONCH3); 3.60 (s, 3H, OCH3); 4.48 (d, 1H, J¼16 Hz,
NCH2C-200); 5.21 (d, 1H, J¼16 Hz, NCH2C-200); 5.64 (s, 1H, H-4); 7.33
(m, 4H, H-20, H-60, H-30, H-50); 7.46 (d, 2H, J¼8.6 Hz, H-3%, H-5%);
7.87 (s, 1H, H-500); 7.97 (d, 2H, J¼8.6 Hz, H-2%, H-6%). 13C NMR
(75 MHz, acetone-d6) d¼16.61 (CH3); 31.34 (CONCH3); 48.31
(NCH2C-200); 51.47 (OCH3); 59.40 (C-4); 104.15 (C-5); 115.46 (C-500);
128.48 (C-2%, C-6%); 129.54 (C-5%, C-3%); 129.47–129.55 (C-20, C-
60, C-30, C-50); 133.90–133.92–133.95 (C-1%, C-40, C-4%); 140.95 (C-
10); 150.87 (C-2); 153.76 (C-6); 154.23 (C-400); 166.30 (CO2CH3);
167.98 (C-200). HRMS, m/z found: 293.0675 (calculated for
4.8.2. 1-[2-[4-(4-Bromophenyl)-1,6-dimethyl-2-oxo-3-
(2H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydropyrimidin-5-
ylcarbonyloxy]ethyl]-3-methylimidazolium hexafluoro-
phosphate (13b)
C
14H14N2O335Cl, [MꢁC10H7NSCl]þ requires: 293.0693), found:
470.0504 (calculated for C23H18N3O325Cl2S, [MꢁOMe]þ requires:
470.0497).
Yield¼71%, brown foam. 1H NMR (300 MHz, DMSO-d6) d¼2.42
(s, 3H, CH3); 3.18 (s, 3H, CONCH3); 3.92 (s, 3H, NCH3); 4.10 (d, 1H,
J¼15 Hz, NCH2C-5%); 4.22–4.43 (m, 4H, NCH2CH2O); 5.14 (d, 1H,
J¼15 Hz, NCH2C-5%); 5.37 (s, 1H, H-40); 7.10 (d, 2H, J¼8.3 Hz, H-200,
H-600); 7.52 (d, 1H, J¼8.3 Hz, H-300, H-500); 7.69 (s, 1H, H-4 or H-5);
7.72 (s, 1H, H-4 or H-5); 9.12 (s, 1H, H-2). 13C NMR (75 MHz, DMSO-
d6) d¼16.10 (CH3); 30.89 (CONCH3); 35.89 (NCH3); 39.18 (NCH2C-
5%); 47.99 (CH2N); 56.41 (C-40); 61.95 (CH2O); 101.46 (C-50); 121.21
(C-400); 122.47–123.86 (C-4, C-5); 128.96 (C-200, C-600); 131.67 (C-300,
C-500); 136.85 (C-100); 139.74 (C-2); 151.57–152.39 (C-20; C-60);
154.64 (C-5%); 164.35 (CO2CH2CH2). 31P NMR (121 MHz, DMSO-d6)
d¼ꢁ143.07 (hept, JP–F¼711 Hz, PFꢁ6 ). HRMS, m/z found: 515.1164
4.7.4. Methyl 4-(4-chlorophenyl)-1,6-dimethyl-3-[(4-(4-methoxy-
phenyl)-1,3-thiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (12d)
Yield¼70%, brown foam. IR (KBr): 1249, 1490, 1670, 1702, 2948,
3101, 3304 cmꢁ1
.
1H NMR (300 MHz, acetone-d6) d¼2.56 (s, 3H,
CH3); 3.31 (s, 3H, CONCH3); 3.60 (s, 3H, OCH3); 3.83 (s, 3H, C-
4%OCH3); 4.40 (d, 1H, J¼16 Hz, NCH2C-200); 5.25 (d, 1H, J¼16 Hz,
NCH2C-200); 5.65 (s, 1H, H-4); 6.98 (d, 2H, J¼8.9 Hz, H-3%, H-5%);
7.34 (q, 4H, J¼7.5 Hz, H-20, H-60, H-30, H-50); 7.64 (s, 1H, H-500); 7.90
(d, 2H, J¼8.9 Hz, H-2%, H-6%). 13C NMR (75 MHz, acetone-d6)
d¼16.62 (CH3); 31.35 (CONCH3); 48.10 (NCH2C-200); 51.48 (OCH3);
55.59 (C-4%OCH3); 59.22 (C-4); 104.24 (C-5); 112.77 (C-500); 114.83
(C-5%, C-3%); 128.21 (C-1%); 128.35 (C-6%, C-2%); 129.48–129.68
(C-20, C-60, C-30, C-50); 134.00 (C-40); 141.06 (C-10); 151.04 (C-6);
153.85 (C-2); 155.71 (C-400); 160.61 (C-4%); 166.43 (CO2CH3); 167.47
(C-200). HRMS, m/z found: 293.0692 (calculated for C14H14N2O335Cl,
[MꢁC11H10NOS]þ requires: 293.0693), found: 205.0546 (calculated
for C11H11N3OS, [MþH]þ requires: 205.0561).
(calculated for
C
21H24N8O739Br, Cþ requires: 515.1158), found:
537.0990 (calculated for C21H23N8O739BrNa, [CꢁHþNa]þ requires:
537.0974).
4.9. Standard procedure for the preparation of compounds
14(a,b) by transesterification of ionic liquid phase bound
3,4-DHPMs 13(a,b)
In a 50 ml round bottomed flask, provided with a magnetic
stirrer and reflux condenser, a mixture of ionic liquid phase 13
(370 mmol, 1 equiv) and commercial sodium methoxide (40 mg,
740 mmol, 2 equiv) in anhydrous methanol (15 ml) was heated at
78 ꢀC for 18 h under vigorous magnetic stirring. After cooling down
to room temperature, the crude reaction mixture was concentrated
in vacuo. To the crude residue was added deionized water (5 ml)
and it was acidified at pH 2 with 3 M hydrochloric acid. The desired
insoluble N-3 functionalized 3,4-DHPM 14 was collected by filtra-
tion and was purified by washings with deionized water (2ꢂ5 ml)
and was further dried under high vacuum (10ꢁ2 Torr) at 25 ꢀC for
3 h. The pure product 14 was characterized by 1H, 13C NMR, and
HRMS.
4.8. Typical procedure for the preparation 1-[2-[4-
(4-halogenophenyl)-1,6-dimethyl-2-oxo-3-(2H-tetrazol-
5-ylmethyl)-1,2,3,4-tetrahydropyrimidin-5-
ylcarbonyloxy]ethyl]-3-methylimidazolium
hexafluorophosphate 13(a,b)
In a 50 ml round bottomed flask, provided with a magnetic
stirrer and reflux condenser, 1-[2-[4-(4-halogenophenyl)-3-
(cyanomethyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-
ylcarbonyloxy]ethyl]-3-methylimidazolium hexafluorophosphate
8 (0.63 mmol), sodium azide (83 mg, 1.26 mmol, 2 equiv), and
ammonium chloride (68 mg, 1.26 mmol, 2 equiv) were dispersed in
dry dimethylformamide (0.5 ml). The reaction mixture was heated
at 110 ꢀC for 24 h under vigorous magnetic stirring, then cooled
down to room temperature. To the crude reaction mixture was
added deionized water (2ꢂ5 ml) and the desired insoluble ionic
liquid phase 13 was collected by filtration, then washed with
deionized water (5 ml). The compound 13 was dried under high
vacuum (10ꢁ2 Torr) at 25 ꢀC for 3 h. The pure product 13 was
characterized by 1H, 13C NMR, and HRMS.
4.9.1. Methyl 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3-
(2H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (14a)
Yield¼92%, brown foam. IR (KBr): 1211, 1655, 1699, 2947, 3284,
3522 cmꢁ1. 1H NMR (300 MHz, DMSO-d6) d¼2.48 (s, 3H, CH3); 3.20
(s, 3H, CONCH3); 3.57 (s, 3H, OCH3); 4.36 (d, 1H, J¼16 Hz, NCH2C-
500); 5.02 (d, 1H, J¼16 Hz, NCH2C-500); 5.42 (s, 1H, H-4); 7.29 (d, 2H,
J¼8.1 Hz, H-20, H-60); 7.40 (d, 1H, J¼8.1 Hz, H-30, H-50). 13C NMR

J.C. Legeay et al. / Tetrahedron 64 (2008) 5328–5335
5335
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Ed.; Elsevier Academic: Amsterdam, 2003; Vol. 38, pp 333–346; (b) Thornber,
C. W. Chem. Soc. Rev. 1979, 8, 563–580.
7. Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; Mc
Creary, A.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; Verveer, P. C.;
Kruse, C. G. J. Med. Chem. 2005, 48, 1823–1838.
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10. Lee, S. Chem. Commun. 2006, 1049–1063.
(75 MHz, DMSO-d6) d¼16.58 (CH3); 31.21 (CONCH3); 39.98
(NCH2C-500); 51.63 (OCH3); 58.38 (C-4); 103.02 (C-5); 129.09–129.14
(C-20, C-60, C-30, C-50); 133.05 (C-40); 140.00 (C-10); 150.49–153.05
(C-2, C-6); 154.09 (C-500); 165.86 (CO2CH3). HRMS, m/z found:
295.0653 (calculated for
quires: 295.0664).
C
14H14N2O335Cl, [MꢁCH2CN3NH]þ re-
11. Fraga-Dubreuil, J.; Famelart, M. H.; Bazureau, J. P. Org. Process Res. Dev. 2002, 6,
374–378.
4.9.2. Methyl 4-(4-bromophenyl)-1,6-dimethyl-2-oxo-3-
(2H-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (14b)
12. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett. 2001, 42, 6097–6100.
13. For a recent review, see: Mia, W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897–908.
14. Le Tao, X.; Lei, M.; Wang, Y. G. Tetrahedron Lett. 2007, 48, 5143–5146.
15. Donga, R. A.; Khaliq-Uz-Zaman, S. M.; Chan, T. H.; Damha, M. J. J. Org. Chem.
2006, 71, 7907–7910.
16. He, X.; Chan, T. H. Synthesis 2006, 1645–1651.
17. He, X.; Chan, T. H. Org. Lett. 2007, 9, 2681–2684.
18. Legeay, J. C.; Goujon, J. Y.; Toupet, L.; Vanden Eynde, J. J.; Bazureau, J. P. J. Comb.
Chem. 2006, 8, 829–833.
19. Temperature measured by an IR captor: Prolabo, French Patent 622 410, 14669
Fr, 1991.
Yield¼96%, brown foam. IR (KBr): 1211, 1459, 1629, 1668, 1702,
2952, 3265, 3635 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6) d¼2.46 (s,
3H, CH3); 3.19 (s, 3H, CONCH3); 3.57 (s, 3H, OCH3); 4.38 (d, 1H,
J¼16 Hz, NCH2C-500); 5.03 (d,1H, J¼16 Hz, NCH2C-500); 5.41 (s,1H, H-
4); 7.22 (d, 2H, J¼8.1 Hz, H-20, H-60); 7.53 (d, 2H, J¼8.1 Hz, H-30,
H-50). 13C NMR (75 MHz, DMSO-d6) d¼16.56 (CH3); 31.19 (CONCH3);
39.97 (NCH2C-500); 51.62 (OCH3); 58.54 (C-4); 102.96 (C-5); 121.63
(C-40); 129.37 (C-20, C-60); 132.04 (C-30, C-50); 140.36 (C-10); 150.46–
153.02 (C-2, C-6); 153.85 (C-500); 165.81 (CO2CH3). HRMS, m/z
found: 337.0174 (calculated for C14H14N2O739Br, [MꢁC2H3N4]þ re-
quires: 337.0188).
20. Commarmot, R.; Didenot, R.; Gardais, J. F. Fr Demande, 25 560 529, 1985; Chem.
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Acknowledgements
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`
One of us (J.C.L.) wishes to thank the ‘Ministere de la Recherche
et de l’Enseignement Superieur’ for a research fellowship. We also
thank Dr. Pierre Guenot (CRMPO) for the mass spectrometry
measurements.
´
´
31. Shiao, M. J.; Lai, L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R. J. Org. Chem. 1993, 58, 4742–
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