A new approach to N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere via ionic liquid-phase technology

Article abstract of DOI:10.1016/j.tetlet.2006.11.148

New N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere were synthesized in six steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology from ILP bound acetoacetate. The 3,4-dihydropyrimidine-2(1H)-

Full text of DOI:10.1016/j.tetlet.2006.11.148

Tetrahedron Letters 48 (2007) 1063–1068
A new approach to N-3 functionalized
3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group
as amide isostere via ionic liquid-phase technology
Jean Christophe Legeay,a Jean Jacques Vanden Eyndeb and Jean Pierre Bazureaua,*
aUniversite´ de Rennes 1, Laboratoire Sciences Chimiques de Rennes, UMR CNRS 6226,
ˆ
Groupe Inge´nierie Chimique et Mole´cules pour le Vivant (ICMV), Bat. 10A, Campus de Beaulieu,
Avenue du Ge´ne´ral Leclerc, CS 74205, 35042 RENNES Cedex, France
bAcade´mie Universitaire Wallonie-Bruxelles, University of Mons-Hainaut, Department of Organic Chemistry,
Faculty of Sciences, 20 Place du Parc, 7000 MONS, Belgium
Received 9 November 2006; revised 23 November 2006; accepted 24 November 2006
Available online 22 December 2006
Abstract—New N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere were synthe-
sized in six steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology from ILP bound acetoacetate. The 3,4-dihydro-
pyrimidine-2(1H)-one (3,4-DHPM) core was prepared in the first step by one-pot three-component Biginelli condensation
followed by N-alkylation with chloroacetonitrile. Then the nitrile group appended on the 3,4-DHPM heterocycle was quantitatively
transformed into amidoxime. Addition of aliphatic carboxylic anhydride or aromatic carboxylic acid to the amidoxime produced the
expected 1,2,4-oxadiazole via the O-acylamidoxime intermediate grafted on the ILP bound 3,4-DHPM using two convergent meth-
ods. After cleavage by transesterification under mild conditions, the target compounds were obtained in good overall yields. The
structures and the purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis.
Ó 2006 Elsevier Ltd. All rights reserved.
Nifedipine is a well-known 1,4-dihydropyridine (DHP)
derivative that is marketed as a drug for the clinical treat-
ment of cardiovascular diseases such as hypertension,
cardiac arrhythmias or angina pectoris.1 Apart from
nifidepine and other second-generation DHP analogs,
interest has also focused on structurally closely related
3,4-dihydro-2(1H)-pyrimidinone analogs (DHPMs),
which exhibit similar biological profiles to DHPs.2
of new functionalized DHPMs with potential and simi-
lar pharmacological profile to classical DHPs calcium
channel modulators has been advocated. The basic idea
here was to replace the amide function in N-3 position
of DHPM by basic 1,2,4-oxadiazole moiety. The 1,2,4-
oxadiazole heterocycle was well known as efficient
amide and/or ester bioisostere4 in peptide mimicry5
and also increased the pharmacological in vitro and
in vivo effects for antiaggregatory and antithrombotic
activity essays.6 It was found to help in the design of
compounds with improved physicochemical properties
and bioavailability.7
Of special interest are the N-3 functionalized DHPMs,
which are known to be excellent calcium channel modu-
lators, for example, the aryl derivatives 1 (SQ 32926)
and 2 (SQ 32547), or a1a adrenergic receptor3 like 3
(SNAP 6201) that are displayed in Figure 1. Due to
the fact that N-3 functionalized DHPM analogs are
pharmacologically rather interesting, the investigation
The advent of combinatorial chemistry, which has pro-
ven particularly useful for multicomponent reactions
such as Biginelli8 and Hantzsch9 condensations, allows
the efficient generation of diverse 3,4-dihydropyrimi-
din-2-one compound libraries that have been subjected
to high throughput screening methods. The use of
polymer supported reagents and scavengers is an attrac-
tive method due to the facile purification process of
removing the excess reagents and side products. On the
other hand, the use of polyethylene glycols (PEGs) and
Keywords: Task-specific ionic liquids; Biginelli; 3,4-Dihydropyrimi-
dine-2(1H)-one; Three-component reaction; Amidoxime; O-Acyl-
amidoxime; 1,2,4-Oxadiazole; Amide isostere; Transesterification;
Cleavage.
*
Corresponding author. Tel.: +33 2 23 23 66 03; fax: +33 2 23 23 63
74; e-mail: jean-pierre.bazureau@univ-rennes1.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.148

1064
J. C. Legeay et al. / Tetrahedron Letters 48 (2007) 1063–1068
NO
2
2/3-NO , 2-CF ,
2
3
2-Cl, 4-Cl
O
O
O
3
R
i-Pr, Et, Me
O
N
NH
2
1
2
R O C
R
2
N
Me
N
H
3
Me
N
H
W
1
O, S, N
1: SQ 32926
F
F
F C
CF
3
3
N
O
O
O
i-PrO C
2
N
O
F
H N
2
N
N
H
N
Me
N
H
S
Et
N
H
O
CO Me
2
2: SQ 32547
3: SNAP 6201
Figure 1. Structure–activity relationship of DHPM calcium channel blockers and biological active DHPM lead compounds.
PEG-grafted polystyrene supports has been employed
successfully because of their homogeneous phase chem-
istry strategies. However, some limitations were
expressed for the use of solid-phase and soluble
polymers such as difficulties to monitor reaction
progress, the large excess of reagents typically used in
solid-phase supported synthesis, low loading capacity
and limited solubility during the reaction progress and
the heterogeneous reaction condition with solid-
phases.10 To circumvent these drawbacks, task-specific
ionic liquids (TSILs), a subclass of usual room temper-
ature ionic liquids (RTILS), have attracted interest as
alternative soluble supports for liquid-phase organic
synthesis11 (LPOS). By introduction of hydroxyl group
on the cation of ionic liquid,12 these ionic liquid-phases
(ILPs) have been used as synthetic equivalents of classi-
cal polymeric matrices in combinatorial chemistry.
These alcohol-functionalized ILPs have been studied
initially in our laboratory13 and by other groups14 in
solution-phase combinatorial synthesis as scavengers.
Continuing our work in this area, we have developed
the synthesis of N-3 functionalized DHPMs with 1,2,4-
oxadiazole group via the three-component Biginelli’s
condensation without solvent, according to the ‘ionic
liquid-phases organic synthesis’ (IoLiPOS) methodology.
In the present letter, we report some preliminary results
on this investigation.
reaction of ILP 3 with tert-butylacetoacetate produced
the transacetoacetyled compound 4 in good yield
(90%) using microwave-assisted solvent-free ionic
liquid-phase synthesis17 (170 °C, 10 min) without the need
of a catalyst as is often used in the literature. Finally, a
mixture constituted by 3 equiv of N-methyl urea 6, para-
halogenobenzaldehyde 5(a,b), ILP bound acetoacetate 4
and a catalytic amount of hydrochloric acid was heated
at 100 °C for 1 h to produce the DHPMs 7(a,b) (93–96%)
grafted on ionic liquid-phases.
With the selected ILP bound 3,4-DHPMs 7(a,b) in
hand, we investigated the possibility of building the
1,2,4-oxadiazole group on N-3 position. The common
methods reported for the preparation of 1,2,4-oxadi-
azoles are cyclization of O-acylamidoximes obtained from
acylation of amidoximes by derivatives of carboxylic
acids18 in the presence of a coupling reagent. The hetero-
cycle is subsequently formed by intramolecular cyclo-
dehydratation. This can be performed either after isolation
of the O-acylated amidoxime precursor or immediately
following its formation in a one-pot reaction. The start-
ing amidoximes19 are accessible by the reaction of
nitriles with hydroxylamine. Our aim was to quickly
develop a convenient, robust and high-yielding reaction
protocol for the introduction of 1,2,4-oxadiazole moiety
on the 3,4-DHPM structure.
As shown in Scheme 1, the key step of our synthetic
strategy toward 3,4-dihydro-2(1H)-pyrimidine 7 is based
on the three-component Biginelli’s reaction with ionic
liquid-phase technology.15 The starting DHPMs 7(a,b)
were chosen as starting compounds for the present
investigation and were conveniently prepared according
to the four step process developed in our group. The
ionic liquid-phase 3 is readily available by solventless
quaternization of methyl imidazole 1 on chloroethanol
at 180 °C for 10 min under microwave16a dielectric heat-
ing (SynthewaveÒ 402 reactor16b) followed by anion-
metathesis of 2 with KPF6 salt. In the third step, the
Initially, our studies commenced by the reaction of ILP
bound 3,4-DHPM 7 and chloroacetonitrile (Scheme 2)
at different reaction temperatures using various bases
(Et3N, Cs2CO3, iPr2NEt) and solvents. The reactions
1
were conveniently monitored by H NMR and among
the conditions studied, we found that treatment of 7
with 2 equiv of ClCH2CN in the presence of NaH20
(2 equiv) in acetonitrile at 0 °C gave good conversion
after 18 h (Table 1). The ionic liquid-phases 8(a,b) were
purified by washing successively with diethyl ether (1/10
w/v), deionised water (1:10 w/v), pentane (1:10 w/v) and
were further dried under high vacuum (10ꢀ2 Torr) at

J. C. Legeay et al. / Tetrahedron Letters 48 (2007) 1063–1068
1065
OH
KPF
Cl
6
OH
Me
Me
N
OH
N
N
N
Me
N
N
, PF
6
, Cl
i
ii
2: [HOC mim][Cl](96%)
3: [HOC mim][PF ](96%)
1
2
2
6
H N
NHMe
2
O
t-BuO
Me
O
X
O
Me
6
5
O
O
Me
N
N
iii
iv
O
O
, PF
6
4: (90%)
O
X
Me
N
Me
O
O
NH
Me
N
N
IL
O
NH
O
, PF
6
Me
N
O
7(a,b)
7a: X = Cl (96%)
7b: X = Br (93%)
Me
X
Scheme 1. Preparation of ionic liquid-phases 7(a,b) bound 3,4-dihydropyrimidine-2(1H)-ones. Reagents and reaction conditions: (i) chloroethanol
(1 equiv), mw, 180 °C, 60 W, 10 min; (ii) KPF6 (1 equiv), MeCN, 25 °C, 18 h; (iii) tert-butyl acetoacetate (2.6 equiv), lx, 170 °C, 150 W, 10 min;
(iv) 100 °C, HCl cat., 60 min.
X
X
X
O
O
O
OH
N
IL
IL
IL
Cl
CN
O
NH
O
O
N
CN
O
N
ii
i
NH
2
Me
N
Me
N
O
Me
N
O
Me
Me
Me
7(a,b)
8(a,b)
9(a,b)
X
X
N
O
O
O
N
IL
IL
N
O
N
O
R
O
N
iii
iv
O
NH
N
O
2
Me
N
O
Me
R
Me
Me
X
N
10(a,b)
11(a-f)
O
N
OH
MeO
Me
12(a-f)
N
Me
N
N
O
N
, PF
6
O
R
Me
ILP 3
Scheme 2. Preparation of N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones 12(a–f). Reagents and reaction conditions: (i) NaH (2 equiv), 0 °C,
MeCN, 18 h; (ii) KOH (1.7 equiv), NH2OH, HCl (1.6 equiv), EtOH, 0 °C, 1 h then reflux, 18 h; (iii) Method A: a. (RCO)2O (20 equiv), 25 °C, 18 h; b.
H2O, reflux, 18 h.; Method B: a. RCO2H (1.09 equiv), DCC (1.02 equiv), DMAP 5%, MeCN, 25 °C, 48 h; b. H2O, reflux, 36 h; (iv) MeONa (1 equiv),
MeOH, reflux, 18 h.
room temperature for 4 h. Next, the nitrile group of 8
was easily transformed into amidoxime 9 by addition
at 0 °C of a solution of hydroxylamine hydrochloride
(1.6 equiv) and potassium hydroxide (1.7 equiv) in etha-
nol followed by moderate reflux for 18 h to achieve
complete conversion (80–82%).

1066
J. C. Legeay et al. / Tetrahedron Letters 48 (2007) 1063–1068
Table 1.
Compound
Starting products
X
R
Yielda (%)
Overall yieldb (%)
7a
7b
5a
5b
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
Cl
Br
Cl
Br
Cl
Cl
—
—
—
—
—
—
Me
Me
Me
Me
Et
Et
96
93
97
93
82
80
91c
98c
80
—
—
—
—
79
74
72
73
58
60
68
60
54
44
45
45
48
45
43
36
8a
8b
7a
7b
9a
9b
8a
8b
10a
10b
11a
11b
11c
11d
11e
11f
12a
12b
12c
12d
12e
12f
9a + (RCO)2O
9b + (RCO)2O
10a
10b
9a + (RCO)2O
9b + (RCO)2O
9a + RCO2H
9b + RCO2H
11a
11b
11c
11d
11e
11f
82
86d
80d
68d
56d
77
p-MeOC6H4
3,4-(CH2O2)C6H3
Me
Me
Et
Et
75
70
75
80
p-MeOC6H4
3,4-(CH2O2)C6H3
81
a Yield of isolated product.
b Overall yield calculated from product 7.
c Prepared according to method A.
d Prepared according to method B.
For the preparation of 1,2,4-oxadiazole 11 grafted on
the ionic liquid-phase, we have studied two experimental
procedures. In the first approach (method A), the reac-
tions were carried out by mixing at room temperature
the ILP bound amidoxime 9(a,b) with excess of aliphatic
anhydride. After 18 h with acetic anhydride as an exam-
ple, these conditions led to the expected O-acylated ami-
doximes 10(a,b) without contamination. The O-acylated
amidoxime derivative 10a (91%), characterized by mass
spectrometry and 1H NMR analyses, was the major
product after purification by diethyl ether washings
(1:10 w/v) to remove acetic acid and excess of anhy-
dride. For the transformation of O-acylated amidoxime
10(a,b) into the corresponding 1,2,4-oxadiazole 11(a,b),
the cyclization took place when the reaction mixture
was heated to reflux in water. It’s noteworthy that there
was no need of a base as a catalyst21 (pyridine, AcONa)
as described in the literature, because the cyclic dehydra-
tion was found to proceed cleanly in good yield (11a:
80% and 11b: 82%) and no cleavage was observed after
analysis of the crude reaction mixture by 1H NMR.
Interestingly, under reaction conditions of method A,
the solventless treatment of ILP bound amidoxime
9(a,b) with propionic anhydride afforded directly the
cyclized 1,2,4-oxadiazole 11(c,d): after 15 h at 25 °C,
the crude O-acylamidoxime intermediate was mixed in
refluxed deionised water to give after work-up the
desired 1,2,4-oxadiazole heterocycle, respectively, in
86% yield for 11c and 80% for 11d.
was easily removed by filtration and the resulting filtrate
was quickly refiltered through a short column of CeliteÒ.
Then, the crude reaction mixture was washed (1:10 w/v)
with AcOEt/Et2O (8/2) to remove excess of the starting
reagents (DCC and carboxylic acid) and 1H NMR anal-
ysis showed that O-acylamidoxime 10 and 1,2,4-
oxadiazole 11 were both observed. Initial attempts to
improve selective preparation of O-acylamidoxime 10
by exploring lower temperature, others solvents, short
reaction times uniformly failed. To achieve complete
cyclization, the resulting crude reaction mixture was
submitted to heating in refluxed deionised water for
36 h. After work-up, the expected ILP bound 1,2,4-
oxadiazoles 11(e,f) were obtained in moderate yields
(56–68%).
As illustrated in Table 1, the versatility of the two meth-
ods24 was demonstrated through the preparation of a
small library of six 1,2,4-oxadiazoles25 11(a–f) grafted
on the ionic liquid phase from aliphatic anhydride or
aromatic carboxylic acid and the products formed were
estimated easily by 1H NMR without detaching the
material from the ionic liquid-phase. These two methods
gave yields ranging from 56% to 86% and overall yields
from 44% to 68%.
In the last step, the target compounds 12 were released
from the ILP bound 1,2,4-oxadiazole 11 by treatment
with 1 equiv of sodium methoxide in refluxed MeOH
for 18 h and again the reaction was easily monitored
1
In the second method (B), we investigated the use of
aromatic carboxylic acid for the in situ preparation of
O-acylamidoxime 10. Acylation of the ILP bound amid-
oxime 9 with carboxylic acid was realized in dry aceto-
nitrile at 25 °C with dicyclohexyl carbodiimide22 (DCC)
and 5% of dimethylaminopyridine23 (DMAP) as cata-
lyst. After 48 h, the insoluble dicyclohexyl urea (DCHU)
by H NMR or TLC. After completion of the cleavage,
the solvent was removed in vacuo. Owing to the small
quantities of the starting ionic ILP bound 1,2,4-oxadi-
azole 11 (5 mmol), the purification and separation of 12
from the starting ILP 3 by the classical washings with
an appropriate solvent are not practicable, but flash-fil-
tration on alumina gel using AcOEt (Rf = 1.0) as eluent

J. C. Legeay et al. / Tetrahedron Letters 48 (2007) 1063–1068
1067
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desired N-3 functionalized 3,4-dihydropyrimidine-
2(1H)-ones 12(a–f) in good yields (70–81%). The struc-
ture of the new 3,4-DHPMs 12 was ascertained by
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In summary, new N-3 functionalized 3,4-dihydropyrim-
idine-2(1H)-ones with 1,2,4-oxadiazole as amide isostere
using ionic liquid-phase organic synthesis (IoLiPOS)
methodology has been developed. To our knowledge,
this new approach has never been reported either in
classical solution-phase reaction or with solid- or
liquid-phase supported organic synthesis. This protocol
involved the attachment of the 3,4-DHPM heterocycle
on the ILP bound acetoacetate by solventless one-pot
three-component condensation. Then, the 3,4-DHPM
intermediates were easily functionalized with 1,2,4-
oxadiazole using two convergent methods from aliphatic
carboxylic anhydrides or from aromatic carboxylic
acids. Detachment by transesterification afforded the
new N-3 functionalized 3,4-DHPMs in good overall
yields. On the basis of this example, the advantages of
the ILP technology26 are that the structure and the pur-
ity of each intermediate could be controlled by standard
spectroscopic methods (1H, 13C NMR, HRMS and IR)
after purification by washings with an appropriate sol-
vent. Owing to the high loading capacity of ILP, in
many cases the use of a large excess of reagents can be
avoided in contrast to the usual solid-phase synthesis
methods. Although a limited number of different and
representative substituents of the 1,2,4-oxadiazole
grafted on the 3,4-DHPM cores are presented here, it
is obvious that a much larger diversity can be easily
achieved. We are currently exploring the scope and
potential of this ILP protocol for the preparation of
new N-3 functionalized 3,4-DHPMs that will be much
more reliable for biological screening.
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Acknowledgments
`
One of us (J.C.L.) thanks the ‘Ministere de la Recherche
´
et de l’Enseignement Superieur’ for a research fellow-
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´
ship. We also thank Dr Pierre Guenot (CRMPO) for
the mass spectrometry measurements and Merck Euro-
lab Prolabo (Fr.) for providing the Synthewave 402Ò
apparatus.
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22. Mathias, L. J. Synthesis 1979, 561–576.
added deionised water (1:15 w/v) and the resulting mixture
was heated at 100 °C for 36 h. After removal of solvent in
vacuo, the desired 1,2,4-oxadiazole 11 was further dried
under high vacuum (10ꢀ2 Torr) at room temperature for
4 h. Products 11 were characterized by 1H, 13C NMR, and
HRMS.
23. Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129–161.
24. General procedure for the preparation of 1,2,4-oxadiazole
11 grafted on ionic liquid-phase bound 3,4-DHPM:
Method A: A mixture of amidoxime 9 (1.04 mmol) and
aliphatic carboxylic anhydride (2 mL) was stirred vigor-
ously at 25 °C for 18 h. Diethyl ether (5 mL) was added to
the reaction mixture and the crude insoluble O-acylami-
doxine was collected by filtration and was purified by
washing with Et2O (1:10 w/v). The purity of O-acyl-
25. Selected data of methyl 4-(4-chlorophenyl)-1,6-dimethyl-
3-[(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (12e): Yield =
81%. White needles, mp = 80–82 °C from EtOH. IR
(KBr): 1260, 1492, 1670, 1700, 2838, 2951 cmꢀ1 1H
.
NMR (300 MHz, CDCl3, TMS) d 2.43 (s, 3H, Me), 3.25
(s, 3H, NMe), 3.56 (s, 3H, OMe), 3.82 (s, 3H, Ar–OMe),
4.02 (d, 1H, J = 16 Hz, N–CH2), 5.18 (d, 1H, J = 16 Hz,
N-CH2), 5.38 (s, 1H, H-4), 6.93 (d, 2H, J = 8.9 Hz, H-3000,
H-5000), 7.16 (m, 4H, H-20, H-30, H-50, H-60), 7.98 (d, 2H,
J = 8.9 Hz, H-2000, H-6000). 13C NMR (75 MHz, CDCl3,
TMS) d 16.59 (Me), 31.20 (CONCH3), 40.96 (NCH2),
51.21 (OCH3), 55.37 (ArOCH3), 57.96 (C-4), 103.61 (C-5),
114.36 (C-3000, C-5000), 116.32 (C-1000), 128.34–128.72 (C-20,
C-30, C-50, C-60), 129.96 (C-2000, C-6000), 133.77 (C-40),
139.04 (C-10), 149.30–153.23 (C-2, C-6), 163.12 (C-4000),
165.83 (CO2Me), 166.98 (C-3000), 175.96 (C-5000). HRMS,
m/z: 481.1251 found (calculated for C24H22N4O535Cl,
[MꢀH]+ requires 481.1279).
1
amidoxime intermediate 10 was controlled by H NMR.
Compound 10 was mixed in refluxed deionised water (1:10
w/v) for 18 h. After removal of solvent in vacuo, the
desired 1,2,4-oxadiazole 11 was further dried under high
vacuum (10ꢀ2 Torr) at room temperature for 4 h. Products
1
11 were characterized by H, 13C NMR, and HRMS.
Method B: To a mixture of dicyclohexylcarbodiimide
(1.02 equiv) and dimethylaminopyridine 5% in dry aceto-
nitrile (15 mL) were added successively amidoxime 9
(0.9 mmol, 1 equiv) in one portion, then aromatic carb-
oxylic acid (1.09 equiv). After vigorous stirring at 25 °C
for 48 h, the insoluble N,N0-dicyclohexylurea (DCHU)
was removed by filtration. The resulting filtrate was
refiltered through a short column of CeliteÒ to remove
some residual DCHU and finally concentrated by rotary
evaporation that gave the expected O-acylamidoxime
intermediate 10. Product 10 was further washed (1:10 w/v)
with a mixture of Et2O/AcOEt (4:1). To product 10 was
26. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron 2003, 59,
6121–6130, ‘Tetrahedron Top-50 Most cited Paper 2003-
2006 Award’, 232nd ACS Full National Meeting ‘Cycle
of Excellence’, San Francisco (USA), September 10,
2006.