Parallel synthesis of 1,2,4-oxadiazoles from carboxylic acids using an improved, uronium-based, activation

Article abstract of DOI:10.1016/S0040-4039(00)02293-0

We describe the synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as an activating agent of the carboxylic acid function for the O-acylation step. This method was used for the synthesis of a library of 24 1,2,4-oxadiazoles.

Full text of DOI:10.1016/S0040-4039(00)02293-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1495–1498
Parallel synthesis of 1,2,4-oxadiazoles from carboxylic acids
using an improved, uronium-based, activation
Re´becca F. Poulain,a,* Andre´ L. Tartara and Benoˆıt P. De´prezb
aLaboratoire de Chimie Organique, UMR 8525, Faculte´ des Sciences Pharmaceutiques et Biologiques, 3 rue du Pr. Laguesse,
F-59006 Lille Cedex, France
bDevgen nv, Technologiepark 9, B-9052 Ghent-Zwijnaarde, Belgium
Received 11 December 2000; accepted 14 December 2000
Abstract—We describe the synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using 2-(1H-benzotriazole-1-yl)-
1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as an activating agent of the carboxylic acid function for the O-acylation
step. This method was used for the synthesis of a library of 24 1,2,4-oxadiazoles. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
anhydrides and orthoesters.8 A synthesis on solid sup-
port using esters has been also published.9
1,2,4-Oxadiazoles have been described as good
bioisosters of ester or amide in a variety of biological
models. In the literature, 1,2,4-oxadiazoles are present
in muscarinic agonists,1 serotoninergic (5-HT3)
antagonists2 and in dopamine (D4) ligands.3 Some com-
pounds have also shown affinities for dopamine, sero-
More recently, the use of carbodiimides like EDC,3–10
DCC10 and DIC11 for the in situ activation of car-
boxylic acids has been reported. This method has even
been used for solid-phase synthesis.11 In the mean time,
an original synthesis via palladium catalysis has been
published.12
tonin
and
norepinephrine
transporters.4
The
1,2,4-oxadiazole ring system has also been used as an
urea bioisoster in b3 adrenergic receptor agonists.5
Some articles have also reported the use of small hete-
rocycles, among which 1,2,4-oxadiazoles, in the design
of dipeptidomimetics.6
2. Results and discussion
We were interested in the synthesis of a library of
1,2,4-oxadiazoles from carboxylic acids and ami-
doximes from a single procedure, with good yields and
purities. Though pyridine is classically used as a sol-
vent, we used DMF which is more desirable for larger
scale synthesis and as a solvent for a large variety of
acids.13
In general, synthesis of 1,2,4-oxadiazoles involves first
the O-acylation step of an amidoxime by an activated
carboxylic acid derivative, followed by cyclodehydra-
tion. Classically, the activated acid derivatives are es-
ters,2 acid chlorides,5–7 symmetrical6 or unsymmetrical1
Table 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02293-0

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R. F. Poulain et al. / Tetrahedron Letters 42 (2001) 1495–1498
Scheme 1. (a) 1 equiv. TBTU, 0.2 equiv. HOBt, 5 equiv. DIPEA in DMF, 1 min, rt; (b) amidoxime, 1 h, rt; (c) DMF, 2 h,
110°C.15
Among the acids selected were some sterically hindered
acids, for example 2-aminoisobutyric acid. It had been
reported that DIC activation for this type of acid gave
the expected 1,2,4-oxadiazoles in poor yields.11 More-
over, carbodiimides are not of friendly use (allergenic)
and are easily deactivated (unless HOBt is used) into
N-acylureas. In an attempt to circumvent these prob-
lems, the use of N,N%-carbonyldiimidazole (CDI) for
both the O-acylation step and the cyclodehydration
steps has been recently reported.14 The results obtained
for three different acids, following this new protocol
with CDI, are shown in Table 1. In our hands, the
expected 1,2,4-oxadiazoles were obtained with poor to
medium yields. Moreover, CDI has a variable shelf-life
and is rapidly hydrolysed in DMF solution.
The O-acylation of amidoximes proceeds in DMF with
1 equivalent of TBTU, in the presence of 0.2 equiv. of
HOBt to accelerate coupling and 5 equivalents of N,N%-
diisopropylethylamine (DIPEA). HOBt can easily be
removed from the mixture by a simple washing with
water. To achieve cyclization, the reaction mixture is
heated at 110°C for 2 h. This method gave moderate to
excellent results for the three acids previously tested
with CDI (Table 1).16
We thus used this versatile procedure for the parallel
synthesis of a library of 24 1,2,4-oxadiazoles.16 As in
the preliminary results, very good yields and purities
were obtained even for sterically hindered acids such as
Aib or o-toluyl acid (Table 2). This method did succeed
with a variety of different acids and amidoximes. In
addition, it allows a very short activation step in com-
parison to the use of CDI. It thus prevents deactivation
of the activated intermediate before the addition of the
amidoxime.
On the contrary, uronium salts are known to be easy to
handle, to have quite fast coupling kinetics and to
display hardly any losses of configuration during cou-
pling. They are also known to enable efficient coupling
of sterically hindered acids and to be soluble in DMF.
We thus developed the use of 2-(1H-benzotriazole-
1 - yl) - 1,1,3,3 - tetramethyluronium tetrafluoroborate
(TBTU) for the synthesis of 1,2,4-oxadiazoles (Scheme
1).
3. Conclusions
A versatile method using uronium activation has been
developed for the solution-phase synthesis of 1,2,4-oxa-
Table 2.

R. F. Poulain et al. / Tetrahedron Letters 42 (2001) 1495–1498
1497
diazoles. This method gives the title compounds with
good yields and purities for all the acids tested. It
can be applied to sterically hindered acids and to
acids whose activated intermediate is not stable. This
versatile protocol could easily be applied to the syn-
thesis of 1,2,4-oxadiazoles in deep-well plates.
(m, 2H); MS=304.4 (MH+). (2): mp=71–76°C; 1H
NMR (DMSO-d6) l 5.56 (s, 2H), 6.99 (t, 1H), 7.07 (d,
2H), 7.31 (t, 2H), 7.50–7.57 (m, 3H), 7.98–8.01 (m,
2H); MS=253.3 (MH+). (3): mp=145–148°C; 1H
NMR (DMSO-d6) l 3.95 (s, 3H), 7.26 (d, 2H), 7.50 (t,
2H), 8.17–8.23 (m, 4H); MS=271.3 (MH+). (4): mp=
125–128°C; 1H NMR (DMSO-d6) l 1.39 (br s, 9H),
1.70 (s, 6H), 7.65 (d, 2H), 8.00 (d, 2H); MS=360.5
(MH+). (5): mp=97.0–101.9; 1H NMR (DMSO-d6) l
1.44 (s, 9H), 1.71 (s, 6H), 7.61–7.67 (m, 3H), 8.07–8.10
(m, 2H); MS=372.4 (MH+). (6): mp=122–125°C; 1H
NMR (DMSO-d6) l 1.44 (s, 9H), 1.71 (s, 6H), 7.69
(dd, 1H), 8.43 (d, 1H), 8.86 (d, 1H), 9.24 (s, 1H);
MS=305.4 (MH+). (7): mp=109–114°C; 1H NMR
(DMSO-d6) l 1.10 (s, 5.5H), 1.31 (s, 3.5H), 1.87–2.00
(m, 3H), 2.20–2.42 (m, 1H), 3.33–3.48 (m, 2H), 5.00–
5.07 (m, 1H), 7.48–7.51 (m, 3H), 7.91–7.97 (m, 2H);
MS=316.4 (MH+). (8): mp=68–73°C; 1H NMR
(DMSO-d6) l 1.09 (s, 5.5H), 1.21 (s, 9H), 1.31 (s,
3.5H), 1.87–1.99 (m, 3H), 2.21–2.32 (m, 1H), 3.30–
3.44 (m, 2H), 4.97–5.05 (m, 1H), 7.48 (d, 2H), 7.84 (d,
Acknowledgements
The authors would like to thank B. Yada, A. Mar-
gogne and D. Hamelin for their helpful assistance
and G. Montagne for NMR spectra.
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2H); MS=372.5 (MH+). (9): mp=147–151°C; H NMR
(DMSO-d6) l 1.25 (s, 4.5H), 1.34 (s, 4.5H), 1.77–1.99
(m, 3H), 2.19–2.30 (m, 1H), 3.25–3.36 (m, 2H), 4.33–
4.37 (m, 1H), 7.76 (d, 2H), 7.87 (d, 2H); MS=384.4
(MH+). (10): mp=50–54°C; 1H NMR (DMSO-d6) l
1.79 (s, 5H), 1.98 (s, 4H), 2.56–2.77 (m, 3H), 2.92–3.05
(m, 1H), 3.99–4.17 (m, 2H), 5.62–5.68 (m, 1H), 8.07
(dd, 1H), 8.89 (d, 1H), 9.29 (d, 1H), 9.76 (s, 1H);
MS=317.4 (MH+). (11): mp=49–50°C; 1H NMR
(DMSO-d6) l 2.60 (s, 3H), 7.34–7.51 (m, 7H), 7.99–8.01
(m, 2H); MS=237.3 (MH+). (12): mp=41–44°C; 1H
NMR (DMSO-d6) l 1.21 (s, 9H), 2.60 (s, 3H), 7.27–
7.38 (m, 2H), 7.47–7.54 (m, 3H), 7.91 (d, 2H), 7.99
(d, 2H); MS=293.4 (MH+). (13): mp=100–104°C; 1H
NMR (DMSO-d6) l 2.48 (s, 3H), 7.20–7.32 (m, 3H),
7.39–7.50 (m, 1H), 7.76–7.82 (m, 2H), 7.93–7.98
1
(m, 2H); MS=303.4 (M−H+). (14): mp=146–151°C; H
NMR (DMSO-d6) l 2.52 (s, 3H), 7.29–7.34 (m, 2H),
7.45–7.52 (m, 2H), 7.99 (dd, 1H), 8.12 (dt, 1H), 8.69
(d, 1H), 8.92 (s, 1H); MS=238.4 (MH+). (15):
mp=108–113°C; 1H NMR (DMSO-d6) l 5.76 (s, 2H),
7.23 (dd, 1H), 7.56 (d, 1H), 7.63–7.71 (m, 4H), 8.11
(dd, 1H); MS=320.2 (M−H+). (16): mp=130–134°C;
1H NMR (DMSO-d6) l 1.39 (s, 9H), 5.75 (s, 2H), 7.23
(dd, 1H), 7.56 (d, 1H), 7.66 (d, 1H), 7.68 (d, 2H),
8.03 (d, 2H); MS=376.3 (M−H+). (17): mp=139–
141°C; 1H NMR (DMSO-d6) l 5.75 (s, 2H), 7.23
(dd, 1H), 7.56 (d, 1H), 7.67 (d, 1H), 8.03 (d, 2H), 8.30
(d, 2H); MS=388.2 (M−H+). (18): mp=120–126°C; 1H
NMR (DMSO-d6) l 5.75 (s, 2H), 7.23 (dd, 1H), 7.56
(d, 1H), 7.67 (d, 1H), 7.71 (dd, 1H), 8.45 (dt, 1H), 8.89
(d, 1H), 9.26 (s, 1H); MS=323.2 (MH+). (19):
mp=117–121°C; 1H NMR (DMSO-d6) l 7.68 (m, 3H),
7.82 (d, 2H), 8.16–8.19 (m, 2H), 8.28 (d, 2H); MS
=255.7 (M−H+). (20): mp=96–99°C; 1H NMR
(DMSO-d6) l 1.40 (s, 9H), 7.68 (d, 2H), 7.79 (d, 2H),
8.08 (d, 2H), 8.25 (d, 2H); MS=313.8 (MH+). (21):
mp=121–125°C; 1H NMR (DMSO-d6) l 7.81 (d, 2H),
8.04 (d, 2H), 8.27 (d, 2H), 8.35 (d, 2H); MS=323.7
(M−H+). (22): mp=133–138°C; 1H NMR (DMSO-d6)
l 7.72 (dd, 1H), 7.82 (d, 2H), 8.28 (d, 2H), 8.50 (d,
1H), 8.90 (d, 1H), 9.32 (s, 1H); MS=258.7 (MH+).
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15. Amidoximes are obtained from nitriles by reaction with
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DIPEA.
6 h) with 1 equiv.
16. All compounds were obtained as powders. Characteri-
zation via: NMR (Bruker DRX-300 MHz); LC/MS
(Micromass Platform LCZ APCI and Diode Array LC
Detection at 200–400 nM); melting points (Bu¨chi
B-450). (1): mp=135–137°C; 1H NMR (DMSO-d6) l
1.44 (s, 9H), 1.71 (s, 6H), 7.61–7.67 (m, 3H), 8.07–8.10
.

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1
(23): mp=144–147°C; H NMR (DMSO-d6) l 7.49–7.60
(m, 6H), 7.74 (t, 1H), 7.86 (t, 1H), 8.22–8.39 (m, 4H), 8.72
(s, 1H), 9.18 (d, 1H); MS=350.4 (MH+). (24): mp=120–
123°C; 1H NMR (DMSO-d6) l 1.40 (s, 9H), 7.51–7.60 (m,
5H), 7.73 (ddd, 1H), 7.85 (ddd, 1H), 8.20 (d, 2H), 8.29 (dd,
2H), 8.69 (s, 1H), 9.18 (d, 1H); MS=406.5 (MH+). (25):
mp=155–157°C; 1H NMR (DMSO-d6) l 7.54–7.62 (m,
3H), 7.79 (t, 1H), 7.88–7.95 (m, 3H), 8.21 (t, 1H), 8.33 (d,
2H), 8.41 (d, 2H), 8.75 (s, 1H), 9.08 (s, 1H); MS=418.4
1
(MH+). (26): mp=163–167°C; H NMR (CDCl3) l 7.50–
7.59 (m, 4H), 7.77 (ddd, 1H), 7.86 (ddd, 1H), 8.25–8.31 (m,
3H), 8.54 (dt, 1H).
.