Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles using ionic liquid-phase organic synthesis (IoLiPOS) methodology

Article abstract of DOI:10.1016/j.tet.2009.11.079

New 3,5-disubstituted 1,2,4-oxadiazoles were synthesized in five steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology. The strategy involved the preparation of amidoxime from the ionic liquid-phase bound arylnitrile. Addition of various car

Full text of DOI:10.1016/j.tet.2009.11.079

Tetrahedron 66 (2010) 986–994
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles using ionic liquid-phase organic
synthesis (IoLiPOS) methodology
a
a
a
a
b
´
Laetitia Duchet , Jean Christophe Legeay , Daniel Carrie , Ludovic Paquin , Jean Jacques Vanden Eynde ,
Jean Pierre Bazureau a
,
*
a
´
´
´
ˆ
Universite de Rennes 1, Laboratoire Sciences Chimiques de Rennes, UMR CNRS 6226, Groupe Ingenierie Chimique & Molecules pour le Vivant (ICMV), Bat. 10A, Campus de Beaulieu,
Avenue du Ge´ne´ral Leclerc, CS 74205, 35042 Rennes Cedex, France
b Universite´ de Mons, De´partement 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:
New 3,5-disubstituted 1,2,4-oxadiazoles were synthesized in five steps by ionic liquid-phase organic
synthesis (IoLiPOS) methodology. The strategy involved the preparation of amidoxime from the ionic
liquid-phase bound arylnitrile. Addition of various carboxylic acid to the amidoxime produced the ex-
pected 3,5-disubstituted 1,2,4-oxadiazoles via the stable O-acyl amidoxime intermediate grafted on the
ionic liquid-phase. The 1,2,4-oxadiazoles were easily cleaved by transesterification under mild reaction
conditions in high purity with good overall yields. The structures of the intermediates in each step were
verified by routine spectroscopic analysis (1H, 13C NMR, and HRMS).
Received 13 October 2009
Received in revised form
16 November 2009
Accepted 18 November 2009
Available online 24 November 2009
Keywords:
Ionic liquid
Ó 2009 Elsevier Ltd. All rights reserved.
Liquid phase
1,2,4-Oxadiazole
Bioisostere
O-acylamidoxime
Amidoxime
1. Introduction
There is a continual need for the development of new technol-
ogies that enable the rapid and efficient construction of biologically
Nitrogen–oxygen heterocyclic derivatives are of synthetic in-
terest because they represent an important class of natural and
non-natural products, many of which exhibit biological activities.
The interest in five-membered systems containing one oxygen and
two nitrogen atoms (positions 1, 2, and 4) relies on from the oc-
currence of 1,2,4-oxadiazoles in biologically active compounds and
natural compounds.1 This motif is often used as an amide or ester
bioisostere.2 Bioisosteric replacement of the amide moiety repre-
sents an area, that is, currently a center of focus because of its
implications in peptide chemistry and the development of pepti-
domimetics.3 The 1,2,4-oxadiazole scaffold is also found in several
drugs and drug leads4 including the metabrotropic glutamate
subtype 5 (mGlu5) receptor antagonist5 A (Fig. 1) and the potent
S1P1 agonist6 B. Compound D showed a promising profile as a lead
compound7 for the endogenous cannabino¨ıd CB2 receptor. Fur-
thermore, derivatives C and E containing 1,2,4-oxadiazole ring
interesting molecules.11 The application of automated methods to
the synthesis of focused libraries to populate screening collections
is an important field of research, particularly for the bio-
pharmaceutical sector. The use of combinatorial chemistry tech-
niques has become common place to generate compounds for the
screening and optimization tools for library generation in drug
discovery.12 Liquid-phase combinatorial synthesis13 offers several
advantages: (i) the large excess of reagents typically used in solid-
supported synthesis is normally not required, (ii) the purification is
possible after each step, (iii) the reactions may be realized in ho-
mogeneous solution, (iv) characterization of immobilized in-
termediates is also straightforward because the soluble polymer
support does not interfere with spectroscopic methods. In recent
years, task-specific ionic liquids (TSILs)14 and ionic liquid-phases
(ILPs)15 da subclass of TSILs as alternative soluble supports for
liquid-phase organic synthesis of small molecules16d are receiving
growing attention due to their tuneable features for various tar-
geted chemical tasks and the advantages as homogeneous sup-
ports. This concept initially developed in our laboratory17 was
successfully used to a wide range of applications18 in solution-
phase combinatorial synthesis.19 In view of the emerging impor-
tance of TSILs as alternatives to classical soluble polymeric matrices
in combinatorial chemistry, our aim in this study was to develop
systems have been identified, respectively, as
b-II-tryptase in-
hibitor8 and serotoninergic (5-HT3).9 Moreover, the 1,2,4-oxadia-
zole nucleus is the core structural unit of the muscarinic agonist10 F.
* Corresponding author. Fax: þ33 223 236 374.
E-mail address: jean-pierre.bazureau@univ-rennes1.fr (J.P. Bazureau).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.079

L. Duchet et al. / Tetrahedron 66 (2010) 986–994
987
O
N
N
H
N
O
N
N
HO C
N
2
N
O
CN
N
O
O
N
O
A: metabotropic glutamate
subtype 5 (mGlu 5)
receptor agonist
B: S1P1 agonist
C: -II-tryptase inhibitor
NH
2
H
N
NH
N
2
N
E: 5-HT antagonist
3
N
N
F
F: muscarinic agonist
O
O
N
N
N
O
H
N
H
N
H
O
N
D: CB agonist
2
Figure 1. Selected biologically active 1,2,4-oxadiazoles.
a novel ionic liquid-phase strategy toward possible bioactive 3,5-
disubstituted 1,2,4-oxadiazoles according to the ‘ionic liquid-phase
organic synthesis (IoLiPOS)’ methodology.
properties of the 1-(2-hydroxyethyl)-3-methyl imidazolium hexa-
fluorophosphate ([HOC2mim][PF6]) in IoLiPOS methodology. The
starting ILP 1 used in Scheme 1, readily available from the reaction
of 1-methylimidazole and 2-chloroethanol, presents a dynamic
viscosity of 336 cPo at 25 ꢀC and a solution like environment for
bound molecules.
2. Results and discussion
For the preparation of the starting ionic liquid-phase bound 4-
cyanobenzoic acid 3, the activation of the carboxylic group by
carbodiimide still constitutes the most frequently used method.
The esterification of 4-cyanobenzoic acid 2 with the ILP 1 in dry
MeCN with 1.1 equiv of dicyclohexyl carbodiimide22 (DCC) and 2%
of 4-dimethylaminopyridine23 (DMAP) as catalyst produced the
functionalized ionic liquid phase 3 in 92% yield (Table 1). During the
work-up, insoluble dicyclohexylurea (DCHU) was eliminated first
by filtration to ensure the final purity of the new functionalized
ionic liquid phase, then on a pad of CeliteÒ to remove the residual
traces of DCHU followed by evaporation of the solvent in vacuo. The
For the preparation of 1,2,4-oxadiazole scaffold, five general
synthetic methods are used: (i) cyclization of the O-acyl amidox-
ime20 formed from reaction of the amidoxime with an acyl chloride
or a carboxylic acid, (ii) condensation of N-acylamidoximes, (iii)
1,3-dipolar cycloaddition of nitrile oxides to nitriles,1 (iv) oxidation
of 4,5-dihydro-1,2,4-oxadiazoles21 and (v) electrocyclic ring closure
of nitrenoids. For this study, the 1,2,4-oxadiazole can be built from
an arylnitrile, hydroxylamine, and a carboxylic acid as building
blocks. Thus, arylnitrile and hydroxylamine are converted into
amidoxime (Fig. 2) and the O-acyl amidoxime is issued from con-
densation of amidoxime with a carboxylic acid.
NH
2
NH
2
N
C
HO
N
N
R
N
H N OH
2
R
O
R
OH
amidoxine
synthesis
O
N
O
O-acyl amidoxine
synthesis
1,2,4-oxadiazole
cyclization
O
Figure 2. Retrosynthetic strategy toward 3,5-disubstituted 1,2,4-oxadiazole.
One of the common transformations in solid-phase organic
synthesis (SPOS), in liquid-phase organic synthesis (LPOS) or in
ionic liquid-phase organic synthesis (IoLiPOS) involves the con-
struction of an ester linkage between solid, liquid or ionic liquid
supported hydroxy or halogen functionality and carboxylic acid
derivative. For this project, the carboxylic function will served as
site of attachment to the ionic liquid-phase. As a suitable model
reaction for ionic liquid-phase supported organic synthesis, we
have chosen to use arylnitrile bound to the ionic liquid moiety
(from commercial 4-cyanobenzoic acid) as novel task-specific ionic
liquid. In this study, we have examined the chemical and physical
crude ILP 3 was washed twice with AcOEt (1:5 w/v) and was further
dried under high vacuum (10ꢁ2 Torr) at 25 ꢀC for 24 h. The ILP 3 was
characterized by mass spectrometry and proton NMR, confirming
that in this esterification the major compound has a molecular ion
corresponding to the appropriate product.
In the second step, the amidoxime 4 was obtained from the ILP
bound arylnitrile 3 by treatment with hydroxylamine hydrochlo-
ride in the presence of potassium hydroxide in ethanol. As illus-
trated in Table 2, the reaction conditions investigated for the
preparation of the amidoxime 4 are presented. Entry 1 shows with
an equivalent mixture of KOH and hydroxylamine (1.5 equiv) gave
NH
2
CN
N
i
ii
iii
O
O
OH
Me
OH
, PF
IL
N
N
OH
IL
IL
CN
N
R
OH
6
O
O
HO
O
O
5(a-j)
1: [HOC mim][PF ]
Ionic Liquid Phase
2
4 (82%)
3 (92%)
2
6
R
R
O
NH
2
N
O
N
N
O
N
iv
v
O
R
O
MeO
IL
IL
IL
OH
O
O
O
O
8(a-j)
6(a-j)
7(a-j)
Scheme 1. Reagent and reaction conditions: (i) 2 1.1 equiv, DCC 1.1 equiv, DMAP 2%, dry MeCN, 25 ꢀC, 24 h. (ii) NH2OH HCl 1.6 equiv, KOH 1.62 equiv, EtOH abs, 0 ꢀC, 30 min, then 3
1 equiv, reflux, 18 h. (iii) DCC 1.02 equiv, DMAP 6–8%, 5 1.1 equiv, dry MeCN, 25 ꢀC, 48 h. (iv) H2O, reflux, 24 h. (v) MeONa 0.75 equiv, MeOH, reflux, 24 h.

988
L. Duchet et al. / Tetrahedron 66 (2010) 986–994
Table 1
Results for the preparation of ionic liquid-phases 3, 4, ionic liquid-phase bound acylated aldoximes 6(a–j) and ionic liquid-phase bound 1,2,4-oxadiazoles 7(a–j)
Product
Starting compounds
R
Yielda (%)
Overall yieldb (%)
3
4
1þ2
3
d
92
82
89
84
90
91
89
85
87
87
85
87
90
90
71
98
93
89
66
97
93
97
d
d
75
67
63
68
68
67
64
65
65
64
65
60
60
64
67
62
57
43
63
60
63
6a
6b
6c
6d
6e
6f
6g
6h
6i
4þ5a
4þ5b
4þ5c
4þ5d
4þ5e
4þ5f
4þ5g
4þ5h
4þ5i
4þ5j
6a
6b
6c
6d
6e
6f
6g
6h
6i
MeCH2
Me(CH2)2
Me(CH2)4
MeOCH2
2-thiophenyl
2-furanyl
5-oxo-2-pyrrolidinyl
p-MeOC6H4
3,4-(MeO)2C6H3
3,4-(CH2O2)C6H3
MeCH2
Me(CH2)2
Me(CH2)4
MeOCH2
2-thiophenyl
2-furanyl
6j
7a
7b
7c
7d
7e
7f
7g
7h
7i
5-oxo-2-pyrrolidinyl
p-MeOC6H4
3,4-(MeO)2C6H3
3,4-(CH2O2)C6H3
7j
6j
CO H
2
CO H
2
O
CO H
2
CO H
2
CO H
CO H
2
2
S
O
5a
5b
5c
5d
5e
5f
O
O
CO H
2
CO H
CO H
2
2
O
CO H
O
2
N
H
O
O
5g
5j
5h
5i
a
Yield of isolated product.
Overall yield calculated from product 1.
b
Table 2
For the synthesis of the target O-acyl amidoxime 6 grafted on
the ionic liquid phase, we examined a series of aliphatic carboxylic
acids 5(a–d), heteroaromatic acids 5(e, f), substituted aromatic
acids 5(h–j) and the heterocyclic acid 5g. After exploring a few sets
of reaction conditions, the one that proved to be the most effective
was the addition of carboxylic acid 5 to a diluted solution of ILP
bound amidoxime 4 in acetonitrile at room temperature with
dicyclohexylcarbodiimide (DCC) and 6–8% of 4-dimethylamino
pyridine. After 48 h and elimination of the insoluble diclohexylurea
(DCHU), the crude ILP bound O-acyl amidoxime 6 was washed with
AcOEt (1:10 w/v) to remove excess of the unreacted starting re-
agents (DCC and carboxylic acid 5) and 1H NMR showed that O-acyl
amidoxime 6 was only observed (Table 3).
Cyclodehydratation (step 4) of ILP bound O-acyl amidoxime 6 to
1,2,4-oxadiazole 7 was carried out in deionized water for 24 h un-
der reflux. After work-up, it is noteworthy that the products 7(a–j)
formed were estimated very easily by 1H NMR without detaching
the material from the ionic liquid phase and examination of the
results in Table 1 showed that the expected 1,2,4-oxadiazoles 7(a–j)
were prepared in good yields (66–98%). After demonstrating the
feasibility of our protocol for the construction of functionalized
1,2,4-oxadiazole grafted on the ILP, we have finally examined the
cleavage of 1,2,4-oxadiazole moiety from the ILP. The target com-
pounds 8(a–j) were easily released from the ionic liquid-phase
bound 1,2,4-oxadiazole 7(a–j) by treatment with sodium meth-
oxide (0.75 equiv) in refluxed methanol. Complete cleavage of the
compounds 7 was easily monitored by thin-layer chromatography
Results of reaction conditions evaluated for the preparation of ionic liquid-phase
bound amidoxime 4
Entry
KOH (equiv)
NH2OH HCl (equiv)
Yielda (%)
86b
82
1
2
3
1.5
1.7
1.7
1.5
1.6
1.4
78
a
Isolated yield.
b
Isolated yield of 4 associated to the amide derivative of 3.
the compound 4 in good yield (86%) associated to the formation of
undesired amide derivative of 3 (<5%) as by-product according to
1H NMR analysis of the crude reaction mixture. It can be observed
that the optimal reaction conditions for compound 4 were obtained
with a stoichiometry of 1:1.7:1.6 of ILP 3/KOH/hydroxylamine to
produce the desired ILP bound amidoxime 4 in good yield (82%).
Purification of amidoxime 4 has been performed by washings (1:10
w/v) successively with cold deionized water and Et2O.
In the third step, our focus was the transformation of the ionic
liquid-phase bound arylamidoxime 4 into O-acyl amidoxime 6.
Existing methods of synthesizing O-acyl amidoxime from carboxylic
acid esters require the presence of strong base, such as NaH24
,
MeONa25, K2CO326 or EtONa27 in refluxing THF, MeOH or EtOH, and
generally give low yields. Acylation of amidoximes by acid chlo-
rides28 have some drawbacks. Acid chlorides are toxic and reactive
chemicals, and only a few acid chlorides are commercially readily
available. Historically, the preferred method of obtaining O-acyl
amidoximes is the reaction of amidoximes with carboxylic acid in
the presence of a coupling reagent, such as DCC, EDCI, CDI, TBTU or
HBTU29 to react with amidoximes.30 Using simple anhydrides as
activated acid derivatives in DMF/pyridine is also a frequently used
method.31
(TLC) or by the observation of a new singlet at
methyl ester group of 8 and also the upfield shift of the
lene protons of the side chain appended on the imidazolium cation
of the ionic liquid-phase [HOC2mim][PF6] 1 from 4.42 ppm to
4.00 ppm in the 1H NMR of the crude reaction mixture. If the peak
d
3.95 ppm for the
a
-methy-
d

L. Duchet et al. / Tetrahedron 66 (2010) 986–994
989
Table 3
from the starting ILP 1 in moderate to good overall yields (35–55%).
Additionally, the ionic liquid-phase [HOC2mim][PF6] 1 issued from
transesterification cleavage can be eventually reused after elution
by MeOH (1/5 w/v).
Results for the preparation of 1,2,4-oxadiazoles 8(a–i) from ionic liquid-phases
7(a–i) after cleavage by transesterification
Product
Starting
product
Yielda Overall
(%)
yieldb (%)
N
O
3. Conclusion
MeO
8a
7a
7b
7c
7d
89
53
N
In summary, we have developed the use of hydroxyl ionic liquid
[HOC2mim][PF6] as soluble support in the liquid-phase organic
synthesis of 3,5-disubstituted 1,2,4-oxadiazole. The ionic liquid-
phase organic synthesis (IoLiPOS) methodology exemplifies the
importance of functionalized ionic liquid-phase combinatorial ap-
proach for lead optimization and offers easy access to compound
collections containing the 1,2,4-oxadiazole moiety. This protocol
involves a facile route to arylnitrile and arylamidoxime grafted on
the ILP. From the ionic liquid-phase bound amidoxime 4 as key
intermediate, O-acylation and cyclodehydration afforded the 1,2,4-
oxadiazoles in high yields and the purity of each intermediate could
be controlled by standard spectroscopic methods (1H, 13C NMR and
HRMS). We are currently exploring the scope and the potential of
the ILP bound amidoxine for the preparation and biological
screening of a wider library.
O
N
O
MeO
8b
82
73
83
49
47
56
N
O
N
O
MeO
8c
N
O
N
N
O
O
O
O
MeO
8d
N
O
MeO
8e
8f
7e
7f
82
84
51
48
N
S
4. Experimental section
4.1. General remarks
O
N
MeO
N
O
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 F-
254 (Merck) or neutral alumina oxide gel 60F 254 (Merck). Visu-
alization was made with ultraviolet light (254 and 365 nm) or with
a fluorescence indicator. 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
O
N
O
MeO
8g
8h
7g
7h
75
83
32
52
N
N
H
O
O
N
O
O
MeO
N
O
O
standard. Data are given in the following order: d value, multiplicity
O
N
(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
MeO
8i
7i
7j
70
87
42
55
N
O
O
N
O
O
MeO
´
for the other compounds in the Center Regional de Mesures Phy-
8j
N
O
siques de l’Ouest (CRMPO, Rennes). Acetonitrile was distilled over
calcium chloride after standing overnight and stored over molec-
ular sieves (3 Å). Solvents were evaporated with a BUCHI rotary
evaporator. All reagents were purchased from Acros, Aldrich Chi-
mie, and Fluka France and were used without further purification.
The starting [HOC2mim][PF6] ionic liquid phase 1 was synthesized
according to our previous method.14
O
a
Yield of isolated product.
Overall yield calculated from product 1.
b
of the a-methylene proton was still present after NMR checking, the
recovered ILP bound 1,2,4-oxadiazole 7 could be resubmitted to the
same reaction conditions until a complete cleavage was achieved.
Normally, the cleavage by transesterification was complete using
the above reaction conditions (MeONa 0.75 equiv/refluxed MeOH)
after 24 h. Owing to the small quantities of the starting ILP bound
1,2,4-oxadiazole 7, the separation and the purification of 8 from the
starting ILP 1 by classical washings with an appropriate solvent are
not practicable, but the use of flash-purification on alumina gel
using CH2Cl2/MeOH (99:1) as eluent afforded the desired 1,2,4-
oxadiazole 8 (Rf¼0.95) as white solid. Importantly, the purity of the
transesterified products 8 cleaved from the ionic liquid-phase was
high enough for NMR (1H, 13C) and mass spectrometry (HRMS)
characterization and no further purification was necessary. As it can
be seen from inspection of the data presented in Table 2, the 1,2,4-
oxadiazoles 8(a–j) were prepared after cleavage in good yields (70–
89%). The target compounds 8(a–j) were synthesized in five steps
4.2. 1-[2-(4-Cyanobenzoyloxy)ethyl]-3-methylimidazolium
hexafluorophosphate (3)
In a 250 ml two-necked round-bottomed flask provided with
a magnetic stirrer and reflux condenser, 1-(2-hydroxyethyl)-3-
methyl-imidazolium hexafluorophosphate 1 (2.97 g, 10.94 mmol)
was mixed in acetonitrile p.a. (150 ml). To this solution was added
successively N,N0-dicyclohexylcarbodiimide DCC (2.46 g, 11.9 mmol,
1.1 equiv) portionwise and dimethylaminopyridine DMAP (26.6 g,
0.21 mmol, 0.2 equiv) in one portion; then, the reaction mixture was
stirred vigorously for 5 min. After, which 4-cyanobenzoic acid 2
(1.77 g,11.92 mmol,1.1 equiv) was added overa periodof 20 min. The
reaction mixture was stirred at room temperature for 24 h and the
insoluble N,N0-dicyclohexylurea (DCHU) was removed by filtration.
The resulting filtrate was refiltered through a short column of CeliteÒ

990
L. Duchet et al. / Tetrahedron 66 (2010) 986–994
to remove some residual DCHU and finally concentrated by rotary
evaporation that gave the expected ionic liquid-phase bound aryl-
nitrile 3. Product 3 was further washed with AcOEt (2ꢂ50 ml) and
was dried under high vacuum (10ꢁ2 Torr) at 25 ꢀC for 4 h.
CH3CH2); 3.86 (s, 3H, NCH3); 4.63–4.65 (m, 4H, OCH2, NCH2); 6.96
(br s, 2H, NH2); 7.71 (m, 1H, H-4); 7.85–7.88 (m, 3H, H-5, H-30, H-50);
3
8.01 (d, 2H, JH,H¼8.4 Hz, H-20, H-60); 9.24 (s, 1H, H-2). 13C NMR
((CD3)2SO):
d
¼8.87 (CH3CH2); 25.52 (CH3CH2); 35.61 (NCH3); 47.62
Yield¼92%, white needles, mp¼147–149 ꢀC. 1H NMR ((CD3)2SO):
(CH2N); 63.11 (OCH2); 122.60 (C-5); 123.47 (C-4); 126.91 (C-30, C-
50); 129.16 (C-20, C-60); 130.43 (C-10); 136.21 (C-40); 136.87 (C-2);
155.34 (N]C–NH2); 164.46 (C]O, C-10); 164.46 (NO–C]O). HRMS,
m/z found: 345.1562 (calculated for C17H21N4O4, Cþ requires:
345.1562).
d
¼3.85 (s, 3H, NCH3); 4.65 (m, 4H, OCH2, NCH2); 7.70 (br s, 1H, H-4);
3
7.85 (br s, 1H, H-5); 8.00 (d, 2H, JH,H¼8.4 Hz, H-30, H-50); 8.10 (d,
2H, 3JH,H¼8.4 Hz, H-20, H-60); 9.20 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼35.77 (NCH3); 47.84 (CH2N); 63.72 (OCH2); 115.68 (C-40); 117.94
(CN); 122.73 (C-5); 123.63 (C-4); 129.96 (C-30, C-50); 132.73 (C-20, C-
60); 132.95 (C-10); 137.02 (C-2); 164.09 (C]O). HRMS, m/z found:
256.1095 (calculated for C14H14N3O2, Cþ requires: 256.1086).
4.4.2. 1-{3-(4-[(Butyloxy)carbamimidoyl]benzoate)ethyl}-3-methyl-
imidazolium hexafluorophosphate (6b). The product 6b was pre-
pared from 200 mg of amidoxime 4 (0.46 mmol, 1 equiv), 95.02 mg
of DCC (0.46 mmol), 4.5 mg of DMAP (0.036 mmol) and 44.63 mg of
butanoic acid 5b (0.506 mmol) according to the standard
procedure.
4.3. 1-[2-[3-[2-Amino-2-(hydroxyimino)methyl]-5-
carbonyloxy]ethyl]-3-methylimidazolium
hexafluorophosphate (4)
Yield¼84%, white needles, mp¼166–168 ꢀC. 1H NMR ((CD3)2SO):
3
3
To
a
solution of potassium hydroxide (1.19 g, 21.2 mmol,
d
¼0.92 (t, 3H, JH,H¼7.3 Hz, CH3CH2); 1.61 (sext, 2H, JH,H¼7.3 Hz,
3
1.62 equiv) in anhydrous ethanol (20 ml), in a 250 ml round-bot-
tomed flask fitted with a reflux condenser, was added portionwise
commercial hydroxylamine hydrochloride (1.45 g, 20.9 mmol,
1.6 equiv) at 0 ꢀC. The reaction mixture was stirred at 0 ꢀC for
30 min. Then, at 25 ꢀC 1-[2-(4-cyanobenzoyloxy)ethyl]-3-methyl-
imidazolium hexafluorophosphate 3 (5.25 g, 13 mmol, 1 equiv) was
dispersed vigorously by magnetic stirring over a period of 20 min.
The reaction mixture was heated at 80 ꢀC for 18 h. To the reaction
media was added cooled deionized water (30 ml) and the desired
unsoluble compound 4 was collected by filtration, then washed
with diethylether (10 ml). The amidoxime 4 was dried under high
vacuum (10–2 Torr) at 25 ꢀC for 4 h.
CH3CH2); 2.45 (t, 2H, JH,H¼7.3 Hz, CH2CO); 3.86 (s, 3H, NCH3);
4.63–4.65 (m, 4H, OCH2, NCH2); 6.95 (br s, 2H, NH2); 7.71 (m, 1H, H-
4); 7.85–7.88 (m, 3H, H-5, H-30, H-50); 8.01 (d, 2H, 3JH,H¼8.3 Hz, H-
20, H-60); 9.21 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼13.46 (CH3CH2);
17.90 (CH3CH2); 34.12 (CH2CO); 35.76 (NCH3); 47.90 (CH2N); 63.24
(OCH2); 122.75 (C-5); 123.62 (C-4); 127.04 (C-30, C-50); 129.28 (C-20,
C-60); 130.53 (C-10); 136.36 (C-40); 137.00 (C-2),155.49 (N]C–NH2);
164.74 (C]O, C-10); 170.58 (NO-C]O). HRMS, m/z found: 359.1715
(calculated for C18H23N4O4, Cþ requires: 359.1719).
4.4.3. 1-{3-(4-[(Hexyloxy)carbamimidoyl]benzoate)ethyl}-3-methyl-
imidazolium hexafluorophosphate (6c). The product 6c was pre-
pared from 200 mg of amidoxime 4 (0.46 mmol, 1 equiv), 95.02 mg
of DCC (0.46 mmol), 4.5 mg of DMAP (0.036 mmol) and 63.4 mg of
hexanoic acid 5c (0.506 mmol) according to the standard
procedure.
Yield¼82%, white needles, mp¼180–182 ꢀC. 1H NMR ((CD3)2SO):
d
¼3.86 (s, 3H, NCH3); 4.62–4.64 (m, 4H, OCH2, NCH2); 5.96 (br s, 2H,
3
NH2); 7.69 (m, 1H, H-4); 7.82 (d, 2H, JH,H¼8.5 Hz, H-30, H-50); 7.84
(m, 1H, H-5); 7.95 (d, 2H, 3J H,H¼8.5 Hz, H-20, H-60); 9.21 (s, 1H, H-2);
9.95 (br s, 1H, OH). 13C NMR ((CD3)2SO):
d
¼35.80 (NCH3); 48.00
Yield¼90%, white needles, mp¼172–174 ꢀC. 1H NMR ((CD3)2SO):
(CH2N); 63.15 (OCH2); 122.78 (C-5); 123.66 (C-4); 125.54 (C-30, C-
50); 129.07 (C-10); 129.23 (C-20, C-60); 137.04 (C-2); 138.01 (C-40);
150.01 (N]C–NH2); 165.01 (C]O). HRMS, m/z found: 289.1301
(calculated for C14H17N4O3, Cþ requires: 289.1300).
d
¼0.86–0.88 (m, 3H, H-500); 1.29–1.31 (m, 4H, H-300, H-400); 1.58–
1.60 (m, 2H, H-200); 2.45–2.47 (m, 2H, H-100); 3.86 (s, 3H, NCH3);
4.63–4.65 (m, 4H, OCH2, NCH2); 6.95 (br s, 2H, NH2); 7.71 (br s, 1H,
3
H-4); 7.85–7.88 (m, 3H, H-5, H-30, H-50); 8.01 (d, 2H, JH,H¼8.3 Hz,
H-20, H-60); 9.21 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼13.77 (C-500);
4.4. Standard procedure for the synthesis of ionic liquid-
phase bound O-acyl amidoxime 6(a–j)
21.76 (C-400); 24.12 (C-200); 30.73 (C-300); 32.21 (C-100); 35.79 (NCH3);
47.94 (CH2N); 63.27 (OCH2); 122.77 (C-5); 123.65 (C-4); 127.07 (C-
30, C-50); 129.32 (C-20, C-60); 130.57 (C-10); 136.38 (C-40); 137.02 (C-
2); 155.56 (N]C–NH2); 164.78 (C]O, C-10); 170.79 (NO–C]O).
HRMS, m/z found: 387.2030 (calculated for C20H27N4O4, Cþ re-
quires: 387.2032).
To a solution of amidoxime 4 (1 equiv), N,N0-dicyclohexyl-
carbodiimide DCC (1.02 equiv) and dimethylaminopyridine DMAP
(0.06–0.08 equiv) in dry acetonitrile (1/8 w/v), was added por-
tionwise carboxylic acid 5 (1.1 equiv) under vigorous magnetic
stirring. The reaction mixture was stirred at 25 ꢀC for 48 h. The
insoluble diclohexylurea (DCHU) was eliminated by filtration on
a filter paper. The resulting filtrate was refiltered though a short
column of CeliteÒ and concentrated by rotary evaporation. Then the
crude residue was further washed with AcOEt (2ꢂ50 ml) to remove
some residual DCC and eventually unreacted carboxylic acid 5. The
desired O-acyl amidoxime 6 was dried under high vacuum (10–
2 Torr) at 25 ꢀC for 3 h. and led to the desired product 6 in 84–91%
yield, which was controlled by 1H and 13C NMR spectroscopy. The
O-acyl amidoxime 6 were stored under inert atmosphere at 4 ꢀC.
4.4.4. 1-{3-(4-[(Methoxyethyloxy)carbamimidoyl]benzoate)ethyl}-3-
methylimidazolium hexafluorophosphate (6d). The product 6d was
prepared from 500 mg of amidoxime 4 (1.15 mmol, 1 equiv),
261.3 mg of DCC (1.26 mmol), 8.4 mg of DMAP (0.069 mmol) and
114 mg of methoxyacetic acid 5d (1.26 mmol) according to the
standard procedure.
Yield¼91%, white needles, mp¼146–148 ꢀC. 1H NMR ((CD3)2SO):
d
¼3.32 (br s, 3H, OCH3); 3.87 (s, 3H, NCH3); 4.26 (s, 2H, COCH2O);
4.63–4.65 (m, 4H, OCH2, NCH2); 7,07 (br s, 2H, NH2); 7.71 (br s, 1H,
3
H-4); 7.85–7.88 (m, 3H, H-5, H-30, H-50); 8.02 (d, 2H, JH,H¼8.1 Hz,
H-20, H-60); 9.22 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼35.78 (NCH3);
4.4.1. 1-{3-(4-[(Propyloxy)carbamimidoyl]benzoate)ethyl}-3-methyl-
imidazolium hexafluorophosphate (6a). The product 6a was pre-
47.91 (CH2N); 58.44 (OCH3); 63.30 (OCH2); 68.26 (CH2O); 122.77 (C-
5); 123.64 (C-4); 127.13 (C-30, C-50); 129.35 (C-20, C-60); 130.71 (C-
10); 136.04 (C-40); 137.02 (C-2),156.19 (N]C–NH2); 164.73 (C]O, C-
10); 168.33 (NO–C]O). HRMS, m/z found: 361.1520 (calculated for
C17H21N4O5, Cþ requires: 361.1512).
pared from 216.2 mg of amidoxime
4 (0.49 mmol, 1 equiv),
96.92 mg of DCC (0.469 mmol), 4.5 mg of DMAP (0.036 mmol) and
39.89 mg of propanoic acid 5a (0.539 mmol) according to the
standard procedure.
Yield¼89%, white needles, mp¼165–169 ꢀC. 1H NMR ((CD3)2SO):
4.4.5. 1-{3-(4-[(Thiophen-2-yloxy)carbamimidoyl]benzoate)ethyl}-
3-methylimidazolium hexafluorophosphate (6e). The product 6e was
3
3
d
¼1.09 (t, 3H, JH,H¼7.5 Hz, CH3CH2); 2.48 (q, 2H, JH,H¼7.5 Hz,

L. Duchet et al. / Tetrahedron 66 (2010) 986–994
991
prepared from 500 mg of amidoxime 4 (1.15 mmol, 1 equiv),
261.3 mg of DCC (1.26 mmol), 8.4 mg of DMAP (0.069 mmol) and
161.5 mg of thiophene-2-carboxylic acid 5e (1.26 mmol) according
to the standard procedure.
(C-200, C-600); 121.30 (C-100); 122.76 (C-5); 123.63 (C-4); 127.20 (C-30,
C-50); 129.30 (C-20, C-60); 130.55 (C-10); 131.62 (C-300, C-500); 136.52
(C-40); 137.04 (C-2); 155.63 (N]C–NH2); 163.00 (C]O, C-10); 163.12
(C-400); 164.74 (NO–C]O). HRMS, m/z found: 423.1666 (calculated
for C22H23N4O5, Cþ requires: 423.1668).
Yield¼89%, yellow needles, mp¼199–201 ꢀC.1H NMR ((CD3)2SO):
d
¼3.87 (s, 3H, NCH3); 4.63–4.65 (m, 4H, OCH2, NCH2); 7.14 (br s, 2H,
NH2); 7.25–7.27 (m,1H, H-400); 7.71 (br s,1H, H-4); 7.87 (br s,1H, H-5);
7.91 (d, 2H, 3JH,H¼8.1 Hz, H-30, H-50); 7.98–7.99 (m,1H, H-300); 8.04 (d,
2H, 3JH,H¼8.1 Hz, H-20, H-60); 8.17–8.19 (m, 1H, H-500); 9.22 (s, 1H, H-
4.4.9. 1-{3-(4-[(3,4-Dimethoxy-benzoyloxy)carbamimidoyl]benzoate)-
ethyl}-3-methylimidazolium hexafluorophosphate (6i). The product 6i
was prepared from 200 mg of amidoxime 4 (0.46 mmol, 1 equiv),
95.2 mg of DCC (0.46 mmol), 4.5 mg of DMAP (0.036 mmol) and
92.3 mg of 3,4-dimethoxybenzoic acid 5i (0.506 mmol) according to
the standard procedure.
2). 13C NMR ((CD3)2SO):
d¼35.77 (NCH3); 47.91 (CH2N); 63.27
(OCH2); 122.76 (C-5); 123.63 (C-4); 127.26 (C-30, C-50); 128.28 (C-400);
129.35 (C-20, C-60); 130.69 (C-10); 132.38 (C-200); 133.84 (C-300);
133.94 (C-500); 136.22 (C-40); 137.01 (C-2); 156.10 (N]C–NH2);
159.53 (NO–C]O); 164.74 (C]O, C-10). HRMS, m/z found: 399.1133
(calculated for C19H19N4O4S, Cþ requires: 399.1127).
Yield¼85%, white needles, mp¼197–199 ꢀC. 1H NMR ((CD3)2SO):
d
¼3.86 (d, 6H, 2ꢂOCH3); 3.87 (s, 3H, NCH3); 4.64–4.66 (m, 4H, OCH2,
NCH2); 7.07 (d, 1H, 3JH,H¼8.7 Hz, H-500); 7.11 (br s, 2H, NH2); 7.60 (d,
1H, 3JH,H¼1.8 Hz, H-200); 7.71 (br s,1H, H-4); 7.84 (d,1H, J¼8.7,1.8 Hz,
H-600); 7.87 (br s,1H, H-5); 7.92 (d, 2H, 3JH,H¼8,4 Hz, H-30, H-50); 8.05
4.4.6. 1-{3-(4-[(Furanyloxy)carbamimidoyl]benzoate)ethyl}-3-meth-
ylimidazolium hexafluorophosphate (6f). The product 6f was pre-
pared from 200 mg of amidoxime 4 (0.46 mmol, 1 equiv), 95.02 mg
of DCC (0.46 mmol), 4.5 mg of DMAP (0.036 mmol) and 62.4 mg of
furane-2-carboxylic acid 5f (0.506 mmol) according to the standard
procedure.
3
(d, 2H, JH,H¼8.4 Hz, H-20, H-60); 9.23 (s, 1H, H-2). 13C NMR
((CD3)2SO):
d
¼35.78 (NCH3); 47.93 (CH2N); 55.65 (2ꢂOCH3); 63.27
(OCH2); 110.96 (C-200); 112.17 (C-500); 121.28 (C-100); 122.78 (C-5);
123.64 (C-4, C-600); 127.26 (C-30, C-50); 129.33 (C-20, C-60); 130.59 (C-
10); 136.55 (C-40); 137.03 (C-2); 148.33 (C-300); 152.89 (C-400); 155.79
(N]C–NH2); 163.31 (C]O, C-10); 164.77 (NO–C]O). HRMS, m/z
found: 453.1773 (calculated for C22H25N4O6, Cþ requires: 453.1773).
Yield¼85%, yellow needles, mp¼83–85 ꢀC. 1H NMR ((CD3)2SO):
d
¼3.87 (s, 3H, NCH3); 4.64–4.66 (m, 4H, OCH2, NCH2); 6.74 (dd, 1H,
JH,H¼3.4, 1.6 Hz, H-400); 7.14 (br s, 2H, NH2); 7.71 (br s, 1H, H-4); 7.74
3
(d, 1H, JH,H¼3.4 Hz, H-300); 7.86 (br s, 1H, H-5); 7.91 (d, 2H,
4.4.10. 1-{3-(4-[(3,4-Methylenedioxy-benzoyloxy)carbamimidoyl]ben-
zoate)ethyl}-3-methylimidazolium hexafluorophosphate (6j). The prod-
uct 6j was prepared from 1 g of amidoxime 4 (2.3 mmol, 1 equiv),
475.1 mg of DCC (2.3 mmol), 16.8 mg of DMAP (0.138 mmol) and
420.5 mg of 3,4-methylenedioxybenzoic acid 5j (2.53 mmol) accord-
ing to the standard procedure.
3JH,H¼8.4 Hz, H-30, H-50); 8.00–8.02 (m, 1H, H-500); 8.04 (d, 2H,
3JH,H¼8.4 Hz, H-20, H-60); 9.23 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼35.78 (NCH3); 47.92 (CH2N); 63.27 (OCH2); 112.12 (C-400); 118.59
(C-300); 122.77 (C-5); 123.63 (C-4); 127.25 (C-30, C-50); 129.36 (C-20,
C-60); 130.71 (C-10); 136.18 (C-40); 137.03 (C-2); 142.85 (C-200);
147.66 (C-500); 155.91 (NO–C]O); 156.10 (N]C–NH2); 164.75
(C]O, C-10). HRMS, m/z found: 383.1348 (calculated for
C19H19N4O5, Cþ requires: 383.1355).
Yield¼87%, white needles, mp¼206–208 ꢀC.1H NMR ((CD3)2SO):
d
¼3.87 (s, 3H, NCH3); 4.64–4.66 (m, 4H, OCH2, NCH2); 6.15 (s, 2H,
OCH2O); 7.05 (d, 1H, 3JH,H¼7.9 Hz, H-500); 7.13 (br s, 2H, NH2); 7.74–
7.76 (m, 3H, H-4, H-200, H-600); 7.87 (br s, 1H, H-5); 7.92 (d, 2H,
3JH,H¼8.1 Hz, H-30, H-50); 8.04 (d, 2H, 3JH,H¼8.1 Hz, H-20, H-60); 9.22
4.4.7. 1-{3-(4-[(5-Oxo-pyrrolidin-3-yloxy)carbamimidoyl]benzoate)-
ethyl}-3-methylimidazolium hexafluorophosphate (6g). The product
6g was prepared from 500 mg of amidoxime 4 (1.15 mmol, 1 equiv),
261.3 mg of DCC (1.26 mmol), 8.4 mg of DMAP (0.069 mmol) and
163.4 mg of 3-oxo-pyrrolidin-carboxylic acid 5g (1.26 mmol)
according to the standard procedure.
(s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼35.78 (NCH3); 47.93 (CH2N);
63.26 (OCH2); 101.97 (OCH2O); 108.10 (C-500); 109.20 (C-200); 122.77
(C-5); 122.83 (C-100); 123.63 (C-4); 125.44 (C-600); 127.23 (C-30, C-50);
129.33 (C-20, C-60); 130.60 (C-10); 136.51 (C-40); 137.02 (C-2); 147.48
(C-300); 151.32 (C-400); 155.65 (N]C–NH2); 162.80 (C]O, C-10);
164.76 (NO–C]O). HRMS, m/z found: 437.1461 (calculated for
C22H21N4O6, Cþ requires: 437.1461).
Yield¼87%, white needles, mp¼179–181 ꢀC. 1H NMR ((CD3)2SO):
d
¼1.90–2.41 (m, 4H, H-400, H-500); 3.86 (s, 3H, NCH3); 4.41 (d, 1H, H-
200); 4.63–4.65 (m, 4H, OCH2, NCH2); 7.13 (br s, 2H, NH2); 7.70 (br s,
1H, H-4); 7.85–7.88 (m, 3H, H-5, H-30, H-50); 8.03 (d, 2H,
3JH,H¼8.1 Hz, H-20, H-60); 8.22 (br s, 1H, NH); 9.22 (s, 1H, H-2). 13C
4.5. Standard procedure for the synthesis of ionic liquid-
phase bound 1,2,4-oxadiazole 7(a–j)
NMR ((CD3)2SO):
d
¼24.23 (C-400); 28.98 (C-500); 35.79 (NCH3); 47.93
(CH2N); 54.16 (C-200); 63.31 (OCH2); 122.78 (C-5); 123.65 (C-4);
127.17 (C-30, C-50); 129.40 (C-20, C-60); 130.77 (C-10); 136.05 (C-40);
137.04 (C-2); 156.25 (N]C–NH2); 164.74 (C]O, C-10); 169.94 (NO–
C]O); 176.99 (C-300). HRMS, m/z found: 400.1622 (calculated for
C19H22N5O5, Cþ requires: 400.1620).
In a 50 ml round-bottomed flask fitted with a reflux condenser
and provided with a magnetic stirrer, the O-acyl amidoxime 6
(1.89 mmol) was dispersed in deionized water (10 ml). The reaction
mixture was heated at 100 ꢀC for 24 h under vigorous stirring. After
cooling down to room temperature over a period of 30 min, the
unsoluble ionic liquid-phase bound 1,2,4-oxadiazole 7 was sub-
mitted to filtration under reduced pressure. The desired compound
7 was further dried under high vacuum at 25 ꢀC for 4 h and was
obtained as white or yellowish needles (excepted for 7g).
4.4.8. 1-{3-(4-[(4-Methoxy-benzoyloxy)carbamimidoyl]benzoate)-
ethyl}-3-methylimidazolium hexafluorophosphate (6h). The prod-
uct 6h was prepared from 1 g of amidoxime 4 (2.3 mmol, 1 equiv),
475.1 mg of DCC (2.3 mmol), 16.8 mg of DMAP (0.138 mmol) and
384.9 mg of 4-methoxybenzoic acid 5h (2.53 mmol) according to the
standard procedure.
4.5.1. 1-{3-[4-(Ethyl-1,2,4-oxadiazol-3-yl)benzoate]ethyl}-3-methyl-
imidazolium hexafluorophosphate (7a). Yield¼90%, white needles,
Yield¼87%, white needles, mp¼203–205 ꢀC.1H NMR ((CD3)2SO):
mp¼116–118 ꢀC. 1H NMR ((CD3)2SO):
d
¼1.34 (t, 3H, JH,H¼7.3 Hz,
3
3
d
¼3.86 (s, 3H, OCH3); 3.87 (s, 3H, NCH3); 4.64–4.66 (m, 4H, OCH2,
CH3CH2); 3.03 (q, 2H, JH,H¼7.3 Hz, CH3CH2); 3.87 (s, 3H, NCH3);
4.64–4.66 (m, 4H, OCH2, NCH2); 7.71 (br s,1H, H-4); 7.86 (br s,1H, H-
5); 8.11–8.13 (m, 4H, H-20, H-30, H-50, H-60, Ar); 9.23 (s, 1H, H-2). 13C
3
NCH2); 7.06 (d, 2H, JH,H¼8.8 Hz, H-200, H-600); 7.10 (br s, 2H, NH2);
7.72 (br s, 1H, H-4); 7.87 (br s, 1H, H-5); 7.92 (d, 2H, 3JH,H¼8.3 Hz, H-
3
30, H-50); 8.04 (d, 2H, JH,H¼8.3 Hz, H-20, H-60); 8.16 (d, 2H,
NMR ((CD3)2SO):
d
¼10.29 (CH3CH2); 19.54 (CH3CH2); 35.78 (NCH3);
3JH,H¼8.8 Hz, H-300, H-500); 9.22 (s, 1H, H-2). 13C NMR ((CD3)2SO):
47.94 (CH2N); 63.36 (OCH2); 122.75 (C-5); 123.68 (C-4); 127.23 (C-30,
d
¼35.77 (NCH3); 47.90 (CH2N); 55.43 (OCH3); 63.25 (OCH2); 113.77
C-50); 130.16 (C-20, C-60); 130.70 (C-40); 131.36 (C-10); 137.03 (C-2);

992
L. Duchet et al. / Tetrahedron 66 (2010) 986–994
164.61 (C]O); 166.72 (C-300); 181.66 (C-500). HRMS, m/z found:
HRMS, m/z found: 365.1246 (calculated for C19H17N4O4, Cþ re-
quires: 365.1249).
327.1455 (calculated for C17H19N4O3, Cþ requires: 327.1457).
4.5.2. 1-{3-[4-(Propyl-1,2,4-oxadiazol-3-yl)benzoate]ethyl}-3-meth-
4.5.7. 1-{3-[4-(3-Oxo-pyrrolidin-2-yl-1,2,4-oxadiazol-3-yl)benzo-
ylimidazolium hexafluorophosphate (7b). Yield¼90%, white needles,
ate]ethyl}-3-methylimidazolium hexafluorophosphate (7g). Yield¼66%,
3
mp¼103–105 ꢀC. 1H NMR ((CD3)2SO):
d
¼0.98 (t, 3H, JH,H¼7.3 Hz,
viscous oil. 1H NMR ((CD3)2SO):
d
¼2.07–2.62 (m, 4H, H-4&tprime, H-
3
CH3CH2); 1.81 (sext, 2H, JH,H¼7.3 Hz, CH3CH2); 2.98 (t, 2H,
3JH,H¼7.3 Hz, CH3CH2CH2); 3.89 (s, 3H, NCH3); 4.65–4.67 (m, 4H,
OCH2, NCH2); 7.72 (br s, 1H, H-4); 7.87 (s, 1H, H-5); 8.11–8.13 (m, 4H,
H-20, H-30, H-50, H-60); 9.23 (s, 1H, H-2). 13C NMR ((CD3)2SO):
5%) 3.88 (s, 3H, NCH3); 4.65–4.67 (m, 4H, OCH2, NCH2); 5.14 (m, 1H,
H-2%) 7.72 (br s, 1H, H-4); 7.84 (br s, 1H, H-5); 8.15 (m, 4H, H-30, H-50,
H-20, H-60, Ar); 8.42 (s,1H, NH); 9.23 (s,1H, H-2). 13C NMR ((CD3)2SO):
d
¼25.80 (C-4%) 28.77 (C-5%) 35.81 (NCH3); 47.94 (CH2N); 49.49 (C-
d
¼13.23 (CH3CH2); 19.41 (CH3CH2); 27.51 (CH3CH2CH2); 35.78
2%) 63.42 (OCH2); 122.77 (C-5); 123.69 (C-4); 127.40 (C-30, C-50);
130.27 (C-20, C-60); 131.63 (C-10); 137.05 (C-2, C-40); 164.59 (C]O);
166.97 (C-500); 176.96 (C-300); 181.01 (C-3&tprime). HRMS, m/z found:
382.1514 (calculated for C19H20N5O4, Cþ requires: 382.1515).
(NCH3); 47.95 (CH2N); 63.36 (OCH2); 122.76 (C-5); 123.68 (C-4);
127.24 (C-30, C-50); 130.16 (C-20, C-60); 130.70 (C-40); 131.37 (C-10);
137.04 (C-2); 164.62 (C]O); 166.75 (C-300); 180.70 (C-500). HRMS, m/z
found: 341.1624 (calculated for C18H21N4O3, Cþ requires: 341.1613).
4.5.8. 1-{3-[4-(4-Methoxyphenyl-1,2,4-oxadiazol-3-yl)benzoa-
4.5.3. 1-{3-[4-(Pentyl-1,2,4-oxadiazol-3-yl)benzoate]ethyl}-3-meth-
te]ethyl}-3-methylimidazolium hexafluorophosphate (7h). Yield¼99%,
ylimidazolium hexafluorophosphate (7c). Yield¼71%, yellowish
white needles, mp¼208–210 ꢀC. 1H NMR ((CD3)2SO):
¼3.86 (s, 3H,
d
needles, mp¼84–86 ꢀC. 1H NMR ((CD3)2SO):
d
¼0.87 (t, 3JH,H¼7.3 Hz,
OCH3); 3.89 (s, 3H, NCH3); 4.65–4.67 (m, 4H, OCH2, NCH2); 7.16
3H, CH3CH2); 1.37 (m, 4H, CH3CH2CH2); 1.79 (quint, 2H, 3JH,H¼7.3 Hz,
CH3CH2CH2CH2); 3.01 (t, 2H, 3JH,H¼7.3 Hz, CH3CH2CH2CH2CH2); 3.87
(s, 3H, NCH3); 4.64–4.66 (m, 4H, OCH2, NCH2); 7.72 (br s, 1H, H-4);
7.87 (br s, 1H, H-5); 8.10–8.17 (m, 4H, Ar, H-20, H-30, H-50, H-60, Ar);
(d, 2H, JH,H¼8.8 Hz, H-2&tprime, H-6%) 7.73 (sl, 1H, H-4); 7.88
3
(br s, 1H, H-5); 8.07–8.09 (m, 6H, H-30, H-50, H-20, H-60, H-3&tprime,
H-5&tprime, Ar); 9.24 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d¼
35.80 (NCH3); 47.93 (CH2N); 55.57 (OCH3); 63.38 (OCH2); 114.92
(C-2&tprime, C-6%) 115.38 (C-1%) 122.77 (C-5); 123.69 (C-4); 127.31
(C-30, C-50); 129.92 (C-5&tprime, C-3%) 130.13 (C-20, C-60); 130.65 (C-
40); 131.38 (C-10); 137.03 (C-2); 163.16 (C-4%) 164.59 (C]O); 167.28
(C-300); 175.56 (C-500). HRMS, m/z found: 405.1580 (calculated for
C22H21N4O4, Cþ requires: 405.1562).
9.22 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d¼13.69 (CH3CH2); 21.58
(CH3CH2); 25.53 (CH3CH2CH2CH2); 25.66 (CH3CH2CH2CH2CH2);
30.45 (CH3CH2CH2); 35.80 (NCH3); 47.93 (CH2N); 63.37 (OCH2);
122.76 (C-5); 123.69 (C-4); 127.28 (C-30, C-50); 130.19 (C-20, C-60);
130.70 (C-40); 131.40 (C-10); 137.02 (C-2); 164.61 (C]O); 166.74 (C-
300); 180.91 (C-500). HRMS, m/z found: 369.1930 (calculated for
C20H25N4O3, Cþ requires: 369.1926).
4.5.9. 1-{3-[4-(3,4-Dimethoxyphenyl-1,2,4-oxadiazol-3-yl)benzoa-
te]ethyl}-3-methylimidazolium hexafluorophosphate (7i). Yield¼93%,
4.5.4. 1-{3-[5-(Methoxymethyl-1,2,4-oxadiazol-3-yl)benzoate]ethyl}-
yellowish needles, mp¼195–197 ꢀC. 1H NMR ((CD3)2SO):
¼3.86–
d
3-methylimidazolium hexafluorophosphate (7d). Yield¼98%, yellow-
3.90 (3ꢂs, 9H, 2ꢂOCH3, NCH3); 4.66 (br s, 4H, OCH2, NCH2); 7.19 (d,
ish needles, mp¼160–162 ꢀC. 1H NMR ((CD3)2SO):
d
¼3.44 (br s, 3H,
1H, JH,H¼8.5 Hz, H-5%) 7.60 (d, 1H, JH,H¼1.9 Hz, H-2%) 7.73 (br s,
1H, H-4); 7.78 (dd, 1H, J¼8.5, 1.9 Hz, H-6%) 7.88 (br s, 1H, H-5); 8.12
3
3
OCH3); 3.88 (s, 3H, NCH3); 4.65–4.67 (m, 4H, OCH2, NCH2); 4.85 (s,
2H, C-5"-CH2O); 7.72 (br s, 1H, H-4); 7.87 (br s, 1H, H-5); 8.15 (q, 4H,
3JH,H¼8.6 Hz, H-20, H-30, H-50, H-60, Ar); 9.23 (s, 1H, H-2). 13C NMR
3
3
(d, 2H, JH,H¼8.4 Hz, H-30, H-50); 8.20 (d, 2H, JH,H¼8.4 Hz, H-20, H-
60); 9.23 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼35.80 (NCH3); 47.92
((CD3)2SO):
d¼37.79 (NCH3); 47.93 (CH2N); 58.76 (OCH3); 63.41
(CH2N); 55.63 (OCH3); 55.75 (OCH3); 63.37 (OCH2); 110.10 (C-2%)
111.94 (C-5%) 115.22 (C-1%) 121.92 (C-6%) 122.77 (C-5); 123.69 (C-
4); 127.36 (C-20, C-60); 130.14 (C-30, C-50); 130.63 (C-40); 131.41 (C-10);
137.02 (C-2); 149.02 (C-4%) 153.05 (C-3%) 164.59 (C]O); 167.32 (C-
300); 175.68 (C-500). HRMS, m/z found: 435.1661 (calculated for
C23H23N4O5, Cþ requires: 435.1668).
(OCH2); 64.39 (C-500-CH2O); 122.76 (C-5); 123.68 (C-4); 127.37 (C-30,
C-50); 130.23 (C-20, C-60); 130.31 (C-40); 131.57 (C-10); 137.03 (C-2),
164.58 (C]O); 166.83 (C-300); 177.25 (C-500). HRMS, m/z found:
343.1405 (calculated for C17H19N4O4, Cþ requires: 343.1406).
4.5.5. 1-{3-[5-(Thiophen-2-yl-1,2,4-oxadiazol-3-yl)benzoate]ethyl}-
3-methylimidazolium hexafluorophosphate (7e). Yield¼93%, yel-
4.5.10. 1-{3-[4-(3,4-Methylenedioxy-phenyl-1,2,4-oxadiazol-3-yl)ben-
lowish needles, mp¼209–211 ꢀC. 1H NMR ((CD3)2SO):
d¼3.89 (s,
zoate]ethyl}-3-methylimidazolium hexafluorophosphate (7j). Yield
3H, NCH3); 4.65–4.67 (m, 4H, OCH2, NCH2); 7.36 (t, 1H, 3JH,H¼8.4 Hz,
H-4&tprime, Ar); 7.73 (br s, 1H, H-4); 7.87 (br s, 1H, H-5); 8.05–8.20
(m, 6H, H-30, H-50, H-3&tprime, H-20, H-60, H-500, Ar); 9.23 (s, 1H, H-
¼97%, yellow needles, mp¼203–205 ꢀC. 1H NMR ((CD3)2SO):
¼3.88
d
(s, 3H, NCH3); 4.65–4.67 (m, 4H, OCH2, NCH2); 6.20 (s, 2H, OCH2O);
7.17 (d, 1H, 3JH,H¼8.2 Hz, H-5%); 7.61 (d, 1H, J¼1.6 Hz, H-2%); 7.73 (br
s,1H, H-4); 7.76 (dd,1H, J¼8.2,1.6 Hz, H-6%); 7.88 (br s,1H, H-5); 8.13
(d, 2H, 3JH,H¼8.5 Hz, H-30, H-50); 8.19 (d, 2H, 3JH,H¼8.5 Hz, H-20, H-60);
2). 13C NMR ((CD3)2SO):
d
¼35.80 (NCH3); 47.93 (CH2N); 63.37
(OCH2); 122.77 (C-5); 123.69 (C-4); 124.21 (C-2%) 127.40 (C-30, C-
50); 129.26 (C-4%) 130.15 (C-20, C-60); 130.24 (C-40); 131.54 (C-10);
133.01 (C-3%) 134.30 (C-5%) 137.03 (C-2); 164.56 (C-500); 167.30
(C]O); 171,39 (C-300). HRMS, m/z found: 381.1021 (calculated for
C19H17N4O3S, Cþ requires: 381.1021).
9.23 (s, 1H, H-2). 13C NMR ((CD3)2SO):
d
¼35.78 (NCH3); 47.90
(CH2N); 63.37 (OCH2); 102.37 (OCH2O); 107.24 (C-2%); 109.19 (C-
5%); 116.68 (C-1%); 122.75 (C-5); 123.67 (C-4); 123.83 (C-6%);
127.32 (C-30, C-50); 130.13 (C-20, C-60); 130.55 (C-40); 131.44 (C-10);
137.01 (C-2); 148.17 (C-4%); 151.66 (C-3%); 164.57 (C]O); 167.30 (C-
300); 175.39 (C-500). HRMS, m/z found: 419.1361 (calculated for
C22H19N4O5, Cþ requires: 419.1355).
4.5.6. 1-{3-[4-(Furan-2-yl-1,2,4-oxadiazol-3-yl)benzoate]ethyl}-3-
methylimidazolium hexafluorophosphate (7f). Yield¼89%, orange
needles, mp¼91–93 ꢀC. 1H NMR ((CD3)2SO):
¼3.88 (s, 3H, NCH3);
d
4.65–4.67 (m, 4H, OCH2, NCH2); 6.86–6.88 (m, 1H, H-4%) 7.64 (d,
3JH,H¼3.1 Hz, 1H, H-3%) 7.72 (br s, 1H, H-4); 7.87 (br s, 1H, H-5);
8.11–8.19 (m, 5H, H-20, H-30, H-50, H-60, H-5%, Ar); 9.23 (s, 1H, H-2).
4.6. Standard procedure for the preparation of compounds
8(a–j) by transesterification of ionic liquid-phase bound 1,2,4-
oxadiazole 7(a–j)
13C NMR ((CD3)2SO):
d
¼35.79 (NCH3); 47.92 (CH2N); 63.38 (OCH2);
113.14 (C-4%) 117.96 (C-3%) 122.75 (C-5); 123.68 (C-4); 127.41 (C-30,
C-50); 130.16 (C-20, C-60, C-10); 131.58 (C-40); 137.03 (C-2); 138.77 (C-
2%) 148.52 (C-5%) 164.55 (C-500); 167.19 (C]O); 167.55 (C-300).
To a solution of compound 7 (600 mmol) in anhydrous metha-
nol (10 ml), in a 50 ml round-bottomed flask fitted with a reflux
condenser, was added commercial sodium methoxide (24.3 mg,

L. Duchet et al. / Tetrahedron 66 (2010) 986–994
993
450
m
mol, 0.75 equiv) in one portion under nitrogen. After vigorous
7.72 (s, 1H, H-500, Ar); 8.15 (d, 2H, 3JH,H¼8.1 Hz, H-3, H-5, Ar); 8.22 (d,
3
stirring at 78 ꢀC for 24 h, the crude reaction mixture was half
concentrated in vacuo. Then, the resulting reaction mixture was
submitted to purification by flash chromatography (column:
B¼1 cm, H¼4 cm) on neutral alumina oxide 90 gel (Merck) using
CH2Cl2/MeOH (99:1) as eluent. The solvent of the desired fraction
(Rf¼0.9) was eliminated by rotary evaporation under reduced
pressure. The 1,2,4-oxadiazole 8 was dried at 25 ꢀC for 3 h under
high vacuum (10ꢁ2 Torr) and was characterized by 1H, 13C NMR and
HRMS.
2H, JH,H¼8.1 Hz, H-2, H-6, Ar). 13C NMR (CDCl3):
d¼52.13 (OCH3);
112.36 (C-400, Ar); 116.69 (C-300, Ar); 127.33 (C-3, C-5, Ar); 129.82 (C-
2, C-6, Ar); 130.29 (C-4, Ar); 132.32 (C-1); 139.69 (C-200, Ar); 146.69
(C-500, Ar); 166.12 (C-50, Ar); 167.62 (C]O); 167.76 (C-30, Ar). HRMS,
m/z found: 270.0637 (calculated for C14H10N2O4, Mþ requires:
ꢃ
270.0640).
4.6.7. Methyl 4-[5-(3-oxo-pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl]benzo-
ate (8g). Yield¼75%, white needles, mp¼166–168 ꢀC. 1H NMR
(CDCl3):
d
¼2.22–2.65 (m, 4H, H-400, H-500); 3.89 (s, 3H, OCH3); 5.13
4.6.1. Methyl 4-(5-ethyl-1,2,4-oxadiazol-3-yl) benzoate (8a). Yield
(m, 1H, H-200); 8.14 (q, 4H, 3JH,H¼8.5 Hz, H-3, H-5, H-2, H-6, Ar); 8.40
¼89%, white needles, mp¼83–85 ꢀC. 1H NMR (CDCl3):
d
¼1.46 (t, 3H,
(br s, 1H, NH). 13C NMR (CDCl3):
d
¼25.75 (C-400); 28.71 (C-500); 49.43
3JH,H¼7.6 Hz, CH3CH2); 2.99 (q, 2H, JH,H¼7.6 Hz, CH3CH2); 3.94
(OCH3); 52.36 (C-200); 127.35 (C-3, C-5, Ar); 129.98 (C-2, C-6, Ar);
132.10 (C-4, Ar); 137.52 (C-1, Ar); 165.44 (C]O); 166.95 (C-50); 176.82
(C-30); 180.91 (C-4", C]O). HRMS, m/z found: 287.0913 (calculated
3
(s, 3H, OCH3); 8.14 (br s, 4H, H-2, H-3, H-5, H-6, Ar). 13C
NMR (CDCl3):
d
¼10.55 (CH3CH2); 20.08 (CH3CH2); 52.09 (OCH3);
for C14H13N3O4, Mþ requires: 287.0906).
ꢃ
127.10 (C-3, C-5, Ar); 129.78 (C-2, C-6, Ar); 130.77 (C-4, Ar); 132.05
(C-1, Ar); 166.16 (C]O); 167.33 (C-30); 180.87 (C-50). HRMS, m/z
found: 232.0851 (calculated for C12H12N2O3, Mþ requires:
4.6.8. Methyl 4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl] benzo-
ꢃ
232.0847).
ate (8h). Yield¼83%, white needles, mp¼163–165 ꢀC. 1H NMR
(CDCl3):
d
¼3.88 (s, 3H, OCH3); 3.94 (s, 3H, CO–OCH3); 7.02 (d, 2H,
4.6.2. Methyl 4-(5-propyl-1,2,4-oxadiazol-3-yl) benzoate (8b). Yield
3JH,H¼8.8 Hz, H-200, H-600, Ar); 8.11–8.17 (m, 4H, H-3, H-5, H-300, H-
¼82%, white needles, mp¼67–69 ꢀC. 1H NMR (CDCl3):
d
¼1.05 (t, 3H,
500, Ar); 8.22 (d, 2H, JH,H¼8.3 Hz, H-2, H-6, Ar). 13C NMR (CDCl3):
3
3JH,H¼7.4 Hz, CH3CH2); 1.90 (sext, 2H, 3JH,H¼7.4 Hz, CH3CH2); 2.93 (t,
d
¼52.08 (OCH3); 55.28 (OCH3); 114.31 (C-200, C-600, Ar); 116.36 (C-
2H, 3JH,H¼7.4 Hz, CH3CH2CH2); 3.93 (s, 3H, OCH3); 8.13 (br s, 4H, H-
100, Ar); 127.20 (C-3, C-5, Ar); 129.77 (C-500, C-300, Ar); 129.86 (C-2,
C-6, Ar); 131.01 (C-4, Ar); 132.05 (C-1, Ar); 163.07 (C-400, Ar);
166.21 (C]O); 167.86 (C-30, Ar); 175.67 (C-50, Ar). HRMS, m/z
2, H-3, H-5, H-6, Ar). 13C NMR (CDCl3):
d¼13.39 (CH3CH2); 19.95
(CH3CH2); 28.23 (CH3CH2CH2); 52.10 (OCH3); 127.12 (C-3, C-5);
129.80 (C-2, C-6); 130.81 (C-4); 132.06 (C-1); 166.18 (C]O); 167.33
(C-30); 180.05 (C-50). HRMS, m/z found: 246.1007 (calculated for
C13H14N2O3, Mþꢃ requires: 246.1004).
found: 310.0944 (calculated for C17H14N2O4, Mþ requires:
ꢃ
310.0953).
4.6.9. Methyl 4-[5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl] ben-
4.6.3. Methyl 4-(5-pentyl-1,2,4-oxadiazol-3-yl) benzoate (8c). Yield
zoate (8i). Yield¼70%, white needles, mp¼135–137 ꢀC. 1H NMR
¼73%, white needles, mp¼83–85 ꢀC. 1H NMR (CDCl3):
d
¼0.92 (t, 3H,
(CDCl3):
d
¼3.94–3.96 (m, 6H, 2ꢂOCH3); 3.99 (s, 3H, OCH3); 6.97 (d,
3JH,H¼6.9 Hz, CH3–CH2–); 1.33–1.46 (m, 4H, CH3-CH2CH2); 1.87
(quint, 2H, 3JH,H¼7.5 Hz, CH3CH2CH2–CH2); 2.94 (t, 2H, 3JH,H¼7.5 Hz,
CH3–CH2–CH2–CH2–CH2); 3.93 (s, 3H, OCH3); 8.13 (br s, 4H, H-2,
1H, 3JH,H¼8.4 Hz, H-500, Ar); 7.65 (d, 1H, 3JH,H¼1.6 Hz, H-200, Ar); 7.81
(dd, 1H, J¼8.4, 1.6 Hz, H-600, Ar); 8.14 (d, 2H, 3JH,H¼8.3 Hz, H-3, H-5,
3
Ar); 8.22 (d, 2H, JH,H¼8.3 Hz, H-2, H-6, Ar). 13C NMR (CDCl3):
H-3, H-5, H-6, Ar). 13C NMR (CDCl3):
d
¼1.60 (CH3–CH2–); 21.93
d
¼52.08 (CH3OCO); 55.84 (OCH3); 55.91 (OCH3); 110.19 (C-200, Ar);
(CH3–CH2–); 26.08 (CH3–CH2–CH2); 26.36 (CH3–CH2–CH2); 30.92
(CH3–CH2–CH2–CH2–CH2); 52.09 (OCH3); 127.12 (C-3, C-5, Ar);
129.79 (C-2, C-6, Ar); 130.82 (C-4, Ar); 132.06 (C-1, Ar); 166.17
(C]O); 167.33 (C-30, Ar); 180.24 (C-50, Ar). HRMS, m/z found:
274.1319 (calculated for C15H18N2O3, Mþꢃ requires: 274.1319).
110.87 (C-500, Ar); 116.36 (C-100, Ar); 121.89 (C-600, Ar); 127.20 (C-2, C-
6, Ar); 129.75 (C-3, C-5, Ar); 130.92 (C-4, Ar); 132.07 (C-1, Ar);
149.07 (C-400, Ar); 152.76 (C-300, Ar); 166.18 (C]O); 167.88 (C-30, Ar);
175.67 (C-50, Ar). HRMS, m/z found: 340.1053 (calculated for
C18H16N2O5, Mþ requires: 340.1059).
ꢃ
4.6.4. Methyl 4-(5-methoxymethyl-1,2,4-oxadiazol-3-yl) benzoate
4.6.10. Methyl 4-[5-(3,4-methylenedioxyphenyl)-1,2,4-oxadiazol-3-
(8d). Yield¼83%, white needles, mp¼109–111 ꢀC. 1H NMR (CDCl3):
yl] benzoate (8j). Yield¼87%, white needles, mp¼206–208 ꢀC. 1H
d
¼3.56 (br s, 3H, CH2OCH3); 3.94 (s, 3H, OCH3); 4.75 (s, 2H, CH2O);
NMR (CDCl3):
d
¼3.89 (s, 3H, OCH3); 6.20 (s, 2H, OCH2O); 7.17 (d, 1H,
8.15 (m, 4H, H-2, H-3, H-5, H-6, Ar). 13C NMR (CDCl3):
d
¼53.13
3JH,H¼8,0 Hz, H-500, Ar); 7.62 (s, 1H, H-200, Ar); 7.77 (d, 1H,
3JH,H¼8.1 Hz, H-600, Ar); 8.16 (q, 4H, 3JH,H¼7.8 Hz, H-3, H-5, H-2, H-6,
(OCH3); 59.45 (CH2OCH3); 64.90 (C-50, CH2O); 127.25 (C-3, C-5, Ar);
129.84 (C-2, C-6, Ar); 130.23 (C-4, Ar); 132.33 (C-1, Ar); 166.10
(C]O); 167.49 (C-30, Ar); 176.07 (C-50, Ar). HRMS, m/z found:
Ar). 13C NMR (CDCl3):
d
¼52.08 (OCH3); 102.06 (OCH2O); 108.19 (C-
500, Ar); 109.29 (C-200, Ar); 122.92 (C-100, Ar); 125.53 (C-600, Ar);
127.32 (C-3, C-5, Ar); 129.42 (C-2, C-6, Ar); 130.69 (C-1, Ar); 136.60
(C-4, Ar); 147.57 (C-300, Ar); 151.41 (C-400, Ar); 162.89 (C]O). HRMS,
248.0786 (calculated for C12H12N2O4, Mþ requires: 248.0797).
ꢃ
m/z found: 324.0764 (calculated for C17H12N2O5, Mþ requires:
ꢃ
4.6.5. Methyl 4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl) benzoate
(8e). Yield¼82%, white needles, mp¼130–132 ꢀC. 1H NMR (CDCl3):
324.0746).
d
¼3.96 (s, 3H, OCH3); 7.22–7.24 (m, 1H, H-400, Ar); 7.68 (d, 1H,
3JH,H¼4.8 Hz, H-300, Ar); 7.97 (d, 3JH,H¼3.5 Hz, 1H, H-500, Ar); 8.16 (d,
2H, 3JH,H¼8.3 Hz, H-3, H-5, Ar); 8.23 (d, 3JH,H¼8.3 Hz, H-2, H-6, Ar).
Acknowledgements
13C NMR (CDCl3):
d
¼52.14 (OCH3); 125.37 (C-400, Ar); 127.31 (C-3, C-
`
Two of us (L.D. and J.C.L.) wishes to thank the ‘Ministere de la
5, Ar); 128.36 (C-500, Ar); 129.81 (C-2, C-6, Ar); 130.53 (C-4, Ar);
131.87 (C-1, Ar); 132.03 (C-300, Ar); 132.24 (C-200, Ar); 166.18 (C-50,
Ar); 167.92 (C]O); 171.44 (C-30, Ar). HRMS, m/z found: 286.0430
(calculated for C14H10N2O3S, Mþꢃ requires: 286.0412).
Recherche et de l’Enseignement Supe´rieur’ for research fellowships.
References and notes
1. Jochims, J. C. In Comprehensive HeterocyclicChemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. V. F., Eds.; Pergamon: London, 1996; Vol. 4; Chapter 4 and references
cited therein, pp 179–228.
2. (a) Diana, G. D.; Volkots, D. L.; Nitz, T. J.; Bailey, T. R.; Long, M. A.; Vescia, N.;
Aldous, S.; Pevear, D. C.; Dutkof, F. J. J. Med. Chem.1994, 37, 2421–2436; (b) Borg, S.;
4.6.6. Methyl 4-(5-furan-2-yl-1,2,4-oxadiazol-3-yl) benzoate (8f). Yield
¼84%, white needles, mp¼136–138 ꢀC. 1H NMR (CDCl3):
¼3.94 (s,
d
3H, OCH3); 6.65 (s, 1H, H-400, Ar); 7.38 (d, 1H, 3JH,H¼2.3 Hz, H-300, Ar);

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