A versatile solid-phase synthesis of 3-aryl-1,2,4-oxadiazolones and analogues

Article abstract of DOI:10.1016/j.tetlet.2006.12.050

We report here the first method to load acidic heterocyclic compounds (1,2,4-oxadiazol-5-one, 1,2,4-oxadiazol-5-thione and 1,2,3,5-oxathiadazol-2-oxide) on a polymer. Using Mitsunobu conditions, these heterocycles were anchored on a 4-hydroxymethyl-3-methoxyphenoxybutyric acid benzhydrylamine (HMPB-BHA) resin. After diversification, compounds can be recovered by a simple treatment in diluted TFA. To illustrate the utility of this procedure, iodophenyl derivatives were anchored on the same resin. A HRMAS-NMR analysis shed light on the reactivity of these heterocycles in Mitsunobu conditions. A subsequent diversification using a Sonogashira coupling produced a small array of novel (arylethynyl)-phenyl-1,2,4-oxadiazol-5-ones.

Full text of DOI:10.1016/j.tetlet.2006.12.050

Tetrahedron Letters 48 (2007) 1479–1483
A versatile solid-phase synthesis of 3-aryl-1,2,4-
oxadiazolones and analogues
Julie Charton,a,b,c Nicolas Cousaert,a,b,c Christophe Bochu,d Nicolas Willand,a,b,c
a,b,c,
a,b,c
*
ˆ
´
´ ´
and Rebecca Deprez-Poulain
Benoıt Deprez
aINSERM U761 Biostructures and Drug Discovery, Lille F-59006, France
bFaculte´ de Pharmacie, Universite´ Lille 2, Lille F-59006, France
cInstitut Pasteur de Lille, Lille F-59000, France
dLARMN, UMR CNRS 8009, Lille F-59006, France
Received 5 November 2006; revised 8 December 2006; accepted 12 December 2006
Available online 16 January 2007
Abstract—We report here the first method to load acidic heterocyclic compounds (1,2,4-oxadiazol-5-one, 1,2,4-oxadiazol-5-thione
and 1,2,3,5-oxathiadazol-2-oxide) on a polymer. Using Mitsunobu conditions, these heterocycles were anchored on a 4-hydroxy-
methyl-3-methoxyphenoxybutyric acid benzhydrylamine (HMPB-BHA) resin. After diversification, compounds can be recovered
by a simple treatment in diluted TFA. To illustrate the utility of this procedure, iodophenyl derivatives were anchored on the same
resin. A HRMAS-NMR analysis shed light on the reactivity of these heterocycles in Mitsunobu conditions. A subsequent diversi-
fication using a Sonogashira coupling produced a small array of novel (arylethynyl)-phenyl-1,2,4-oxadiazol-5-ones.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
different lipophilic properties that may translate into
improved bioavailability compared with their tetrazole
analogues.4 In our project aiming at synthesizing vari-
ous analogues of pharmacologically active carboxylic
acids, that would display different pKas and lipophilic-
ity, we explored the use of solid supported reactions per-
formed on polymer-linked heterocycles. In particular,
we focused on 1,2,4-oxadiazol-5-one, 1,2,4-oxadiazol-
5-thione and 1,2,3,5-oxathiadiazol-2-oxide. This strat-
egy is inspired from solid phase peptide synthesis and
retains from it the advantage of both the tractability
of polymer supported chemistry and a single step for
protection and anchoring of the acidic group. This strat-
egy has been previously used for tetrazoles using a trityl
chloride resin.5 Here we describe and compare the use of
two electrophilic resins: a trityl chloride resin and a
HMPB-BHA resin (4-hydroxymethyl-3-methoxy-pheno-
xybutyric acid benzhydrylamine), the latter being used
under Mitsunobu conditions. Anchoring on the HMPB-
BHA resin was successfully applied to the synthesis of 3-
(ethynyl-phenyl)-4H-[1,2,4]oxadiazol-5-one derivatives.
Various acidic heterocycles are classically used by
medicinal chemists as carboxylic acid bioisosters.1
Among these heterocycles, tetrazole is a key pharmaco-
phoric group of the sartan family (antagonists of Angio-
tensin receptor).2 It has also been incorporated into
numerous biologically active series such as leukotriene
antagonists, growth hormone secretagogues or metallo-
b-lactamase inhibitors.3 Other examples of acidic
heterocycles are 1,2,4-oxadiazol-5-one, 1,2,4-oxadiazol-
5-thione and 1,2,3,5-oxathiadiazol-2-oxide rings. In
particular, 1,2,4-oxadiazol-5-one is found in AT1 antag-
onists, COX inhibitors, PLA2 inhibitors and modula-
tors of GluR.4 All these heterocycles can replace
carboxylic acids but display geometrically different
protomers and slightly different physico-chemical
properties. Indeed, as shown in Table 1 on prototypal
molecules, the pKas of these heterocycles range between
3 and 5. Compounds bearing these heterocycles have
Keywords: Acidic heterocycles; Solid phase; Mitsunobu reaction;
Attachment; Cleavage; Sonogashira coupling.
2. Preparation of prototypal heterocyclic compounds
*
Corresponding author. Address: 3 rue du Pr. Laguesse, 59006 Lille
Cedex, France. Tel.: +33 320 964024; fax: +33 320 964 709; e-mail:
benoit.deprez@univ-lille2.fr
Compounds 3–5 (Table 1) were synthesized using classi-
cal solution phase procedures.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.050

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J. Charton et al. / Tetrahedron Letters 48 (2007) 1479–1483
Table 1. Acidic heterocycles used as carboxylic acid bioisosters and their pKa values
Compound
pKa
O
1
2
3
4
5
Benzoic acid
4.2a
O
H
N
N
5-Phenyl-1H-tetrazole
4.5b
5.3c
3.2c
4.8c
N
N
H
N
O
3-Phenyl-4H-[1,2,4]oxadiazol-5-one
3-Phenyl-4H-[1,2,4]oxadiazol-5-thione
4-Phenyl-3H-[1,2,3,5]oxathiadiazole 2-oxide
N
H
O
S
N
O
N
H
N
O
S
N
H
O
a From Ref. 18.
b From Ref. 19.
c pKas were determined in H2O–MeOH (1:1) by potentiometric titration using 0.025 M NaOH.
condensation of 6 with thionyl chloride in the presence
CDI, DBU
dioxane
reflux, 3 h.
67-80%
of pyridine.8
N
3 : R = H
9 : R = I (meta)
10 : R = I (para)
O
O
CN
R
R
N
H
O
S
R = H, I
NH2OH.HCl
DIEA, EtOH
reflux, 6-12 h
66-82%
TCDI, DBU
CH3CN
reflux, 1-3 h.
70-74%
3. Development of a loading method with prototypal
compounds 3–5 on a solid support
N
4 : R = H
11 : R = I (para)
N
OH
R
N
H
In the following section, we describe various anchoring
schemes using trityl chloride or HMPB-BHA resins.
R
NH2
SOCl2, pyridine
THF, room temp.
30-60 min
78%
6 : R = H
7 : R = I (meta)
8 : R = I (para)
N
O
S
5
3.1. Method 1: loading on a trityl chloride resin
N
H
O
Reactions with the trityl chloride resin were performed
using the alkylation conditions reported for the tetrazole
ring.5 (Scheme 2). In these conditions, only 3-phenyl
1,2,4-oxadiazole-5-thione (4) could be successfully
anchored and recovered (Table 2). This result could be
explained by the higher nucleophilicity of the sulfur-con-
taining compound (4) compared to O- and N-nucleo-
philes in 3 and 4.
Scheme 1. Synthesis of prototypal heterocyclic compounds.
As described in Scheme 1, amidoximes 6–8 were pre-
pared by the addition of hydroxylamine to the corre-
sponding nitrile.6 1,2,4-oxadiazol-5-one 3 was obtained
by treatment with 1,10-carbonyldiimidazole (CDI) and
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).7 1,2,4-oxa-
diazol-5-thione 4 was obtained via a similar route from
6 with 1,10-thiocarbonyldiimidazole (TCDI) and DBU.
1,2,3,5-Oxathiadiazol-2-oxide 5 was prepared by the
Two attachment positions for heterocycles 3 and 4 may
occur: via the N4 atom and via the exocyclic oxygen
atom in 3 or via the exocyclic sulfur atom in 4.
Ph
Ph
N
N
3, 4 or 5 (3 equiv.)
X
O
NEt3 (5 equiv.)
TFA (1 or 5%)
CH2Cl2, room temp.,
2 h.
Y
DMF, room temp.,
Ph
12-24 h.
Cl
+
3 : X = C; Y = O
4 : X = C; Y = S
5 : X = S; Y = O
HN
N
Ph
Ph
Ph
X
O
Y
Y
O
N
N
3 : X = C; Y = O
4 : X = C; Y = S
5 : X = S; Y = O
Scheme 2. Loading/cleavage of prototypal compounds 3–5 on trityl-chloride resin.

J. Charton et al. / Tetrahedron Letters 48 (2007) 1479–1483
1481
Table 2. Overall yields of loading/cleavage of prototypal compounds
3–5 on trityl-chloride resin
4.1. Loading of iodinated precursors and insight on their
reactivity towards the alcohol function of the polymer
under Mitsunobu conditions
Compound
Cleavage:
% TFA
Isolated
Purity (%)
(215 nM)
yield (%)
Heterocycles 9 and 10 were loaded on the HMPB-BHA
resin using the Mitsunobu conditions described in
Scheme 3. Unreacted products were easily recycled.
The loading was followed by HRMAS NMR (high res-
olution magic angle spinning NMR), a non-destructive
technique that allows to monitor chemical reactions on
a solid support.12 1H HRMAS NMR spectrum of 10
bound to the resin showed that the loading was
quantitative.13 However, two distinct populations, cor-
responding to two attachment positions of the 1,2,4-
oxadiazol-5-one heterocycle (O- or N4-alkylation) could
be observed.13,14 A HRMAS spectrum of the resin after
acidic cleavage showed that only one population of 10
had been released. It was not possible to unambiguously
identify which population (O- or N4-anchored)
remained on the resin using solely HRMAS NMR.
Compound 12 that closely mimics 10 when bound to
the linker via N4 was prepared using solution phase
chemistry (Fig. 1). Comparison of its NMR spectrum
with the HRMAS spectrum of 10 bound to the resin
showed that only the O-anchored population can be
released from the resin.15
3
4
5
5
5
1a
0
75
0
—
99
—
a Compound 5 was unstable under 5% TFA conditions.
3.2. Method 2: loading on a HMPB-BHA resin
In a second attempt to anchor 3 and 5 on a solid sup-
port, we selected the HMPB-BHA resin, a primary ben-
zylalcohol resin. In acidic media this resin generates a
highly stabilized benzylic cation which is expected to
ease the cleavage step.
Mitsunobu conditions have been reported for the solu-
tion phase alkylation of tetrazoles.9 To our knowledge,
only one report describes a solution phase alkylation
of 1,2,4-oxadiazol-5-one with Mitsunobu conditions,
although in poor yields.10 In our experiments, triphenyl-
phosphine (PPh3) and diisopropyl-azodicarboxylate
(DIAD) were used to anchor compounds 3–5 on the
HMPB-BHA resin.
Conversely, a homogeneous population of 1,2,4-oxa-
diazol-5-thione 11 bound to the resin was observed by
HRMAS. As expected, the heterocyclic ring is anchored
via the exocyclic sulfur atom. This was confirmed by
comparing the solution phase spectrum of 13 (Fig. 1)
and the HRMAS spectrum of 11 bound to the resin.
As reported in Table 3, these conditions proved to be
efficient and allowed to recover the heterocycle in good
yields and high purity. Interestingly, heterocycle 4 was
loaded and recovered in a higher yield.
4. Application to the synthesis of acetylenic derivatives
bearing the 1,2,4-oxadiazol-5-one ring
All these observations are summarized in Scheme 4, and
explain the moderate and very good yields obtained for
1,2,4-oxadiazol-5-one (3) and 1,2,4-oxadiazol-5-thione
(4), respectively (Table 3).
To demonstrate the usefulness of method 2 (iodophenyl)
1,2,4-oxadiazole-5-one 9 and 10 (Scheme 1) were loaded
on a HMPB-BHA resin. Iodophenyl derivatives are
versatile reagents that can be engaged in a variety of
metallo-catalyzed reactions, under non-acidic conditions,
to generate structural diversity through the formation of
new CC bonds.11
4.2. Solid-phase Sonogashira coupling with polymer-
supported 9 and 10
Supported compounds 9 and 10 were reacted with vari-
ous alkynes via a Sonogashira coupling, as described in
O
O
O
O
Table 3. Overall yields of loading/cleavage of prototypal compounds
3–5 on HMPB-BHA resin
H3C
I
H3C
CH3
CH3
Compound
Cleavage:
% TFA
Isolated
Purity (%)
(215 nM)
N
S
N
O
yield (%)
I
12
O
O
N
13
N
3
4
5
5
5
1a
48
70
45
97
97
96
Figure 1. Structure of soluble analogues of polymer-bound 10 and 11
used for NMR assignments (detailed experimental procedure available
in Supplementary data).
a Compound 5 was unstable under 5% TFA conditions.
3, 4 or 5 (3 equiv.)
O
O
O
O
H
N
TFA (1 or 5%)
CH2Cl2,
room temp., 3 h.
PPh3 (4 equiv.)
Y
X
DIAD (4 equiv.)
THF, room temp.
12-24 h.
O
N
HMPB-BHA resin
OH
Y
N
N
3 : X = C; Y = O
4 : X = C; Y = S
5 : X = S; Y = O
X
O
Scheme 3. Loading/cleavage of prototypal compounds 3–5 on HMPB-BHA resin.

1482
J. Charton et al. / Tetrahedron Letters 48 (2007) 1479–1483
Scheme 5.16 Compounds 14–16 and 17–19 were ob-
O
O
tained, respectively, from 9 and 10 after acidic cleavage
and precipitation in a dichloromethane/petroleum ether
mixture. Overall yields (three steps: loading, Sonogash-
ira, cleavage) were satisfactory and purities were excel-
lent (Table 4). No iodinated precursor (9 or 10) could
be detected after cleavage showing that the Sonogashira
coupling was quantitative.17 No further purification was
required.
TFA (5%) / CH2Cl2
O
N
N
I
N-anchored (50%)
+
O
H
N
O
O
HMPB-BHA resin
Mitsunobu conditions
I
O
O
N
10
TFA (5%) / CH2Cl2
O
N
I
O
N
O-anchored (50%)
5. Conclusion
O
O
H
N
We have shown that 1,2,4-oxadiazol-5-one and -thione,
as well as 1,2,3,5-oxathiadiazol-2-oxide can be loaded
on benzylalcohol resin using Mitsunobu conditions
and retrieved from the polymer in good to excellent
yields under mild acidic conditions. This anchoring has
been shown to be compatible with solid-phase Sono-
gashira coupling conditions to produce a small array
of (arylethynyl)phenyl-1,2,4-oxadiazol-5-ones. This
method could find applications in medicinal chemistry,
for the rapid polymer-supported synthesis of carboxylic
acid surrogates.
S
HMPB-BHA resin
Mitsunobu conditions
I
O
S
N
N
11
I
TFA (5%) / CH2Cl2
O
N
S-anchored (100%)
Scheme 4. Summary of the different anchoring modes of 1,2,4-
oxadiazol-5-one or 1,2,4-oxadiazol-5-thione (evidenced by HRMAS
NMR on para-iodo compounds 10 and 11).
1) alkyne (20 equiv.)
PdCl2(PPh3)2 (1.1 equiv.)
CuI (2.2 equiv.)
O
O
H
N
O
DIEA (30 equiv.)
DMF, room temp., 3 h.
Acknowledgements
O
O
N
N
N
2) TFA (5%) / CH2Cl2
room temp., 3 h.
O
R
14-19
´
We thank Andre Tartar for thoughtful comments and
I
discussions. The authors would like to thank ARH
Nord Pas de Calais for the financial support of NC.
We are grateful to the institutions that support our lab-
Scheme 5. Synthesis of compounds 14–19 via solid-phase Sonogashira
coupling.
´
oratory (Inserm, Universite de Lille2 and Institut Pas-
´
teur de Lille, Region Nord-Pas de Calais, EC).
Table 4. Structures and yields of compounds 14–19
Compound
Isolated
Mp (°C)
247–249
216–218
230–231
yielda (%)
Supplementary data
H
N
O
14
15
16
35
30
32
Full experimental details for 3–19, as well as details for
O
1
N
resins loading, H HRMAS NMR data and solid-phase
Sonogashira coupling. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.12.050.
H
N
O
O
N
O
O
N
H
N
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N
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