An improved synthesis of 1,2,4-oxadiazoles on solid support

Article abstract of DOI:10.1016/S0960-894X(01)00028-2

The use of tetra-N-butylammonium fluoride (TBAF) as a mild and efficient reagent for the cyclodehydration of O-acyl amidoximes has been extended to the synthesis of 1,2,4-oxadiazoles on solid support. Argopore MB-CHO resin (Argonaut Technologies) was redu

Full text of DOI:10.1016/S0960-894X(01)00028-2

Bioorganic & Medicinal Chemistry Letters 11 (2001) 753±755
An Improved Synthesis of 1,2,4-Oxadiazoles on Solid Support
Kenneth D. Rice* and John M. Nuss
Departments of Medicinal and Combinatorial Chemistry, Exelixis, Inc., 170 Harbor Way, POBox 511,
South San Francisco, CA 94083-0511, USA
Received 28 November 2000; accepted 3 January 2001
AbstractÐThe use of tetra-N-butylammonium ¯uoride (TBAF) as a mild and ecient reagent for the cyclodehydration of O-acyl
amidoximes has been extended to the synthesis of 1,2,4-oxadiazoles on solid support. Argopore MB-CHO resin (Argonaut Tech-
nologies) was reductively aminated and subsequently acylated with 4-cyanobenzoyl chloride. Conversion of the nitrile to the ami-
doxime and acylation with a range of acid chlorides in parallel followed by treatment with TBAF under ambient conditions
a€orded a library of 3,5-disubstituted 1,2,4-oxadiazoles. # 2001 Elsevier Science Ltd. All rights reserved.
3,5-Functionalized 1,2,4-oxadiazoles have received con-
siderable attention in the pharmaceutical industry as
heterocyclic amide and ester isosteres.1 Furthermore,
oxadiazoles have been employed in the design of
numerous biologically active templates. Examples
include muscarinic agonists,2 tyrosine kinase inhibitors,3
antiin¯ammatory agents,4 histamine H3 antagonists,5
antitumor agents,6 and monoamine oxidase inhibitors.7
Our desire to incorporate this useful template into
diverse combinatorial screening libraries has led to the
examination of tetra-N-butylammonium ¯uoride
(TBAF) induced O-acylamidoxime cyclodehydration on
solid support. The use of TBAF as an ecient and
catalytic reagent for the synthesis of 3,5-disubstituted
1,2,4-oxadizoles from O-acylamidoximes has been
recently reported.8 Alternative approaches to the syn-
thesis of oxadiazoles on solid support have been repor-
ted independently and typically rely on the thermal
cyclodehydration of O-acylamidoximes at elevated tem-
peratures.9,10 In one report, the use of excess sodium
ethoxide in ethanol a€orded the desired oxadiazole at
ambient temperature, but only on extended reaction
times.11 Herein we report that the use of TBAF
readily and eciently a€ords 3,5-disubstituted oxa-
diazoles on solid support at room temperature.
aminated by treatment with an excess of benzylamine in
trimethylorthoformate, followed by imine reduction
using sodium cyanoborohydride.12 Benzylamine acyla-
tion was carried out by reacting the amine resin with a
DMF solution of 4-cyanobenzoyl chloride in the pres-
ence of pyridine and catalytic DMAP. The resin bound
nitrile thus obtained was then eciently converted to
the amidoxime by treatment with an excess of 50%
aqueous hydroxylamine in re¯uxing ethanol over 1 h.
Acylation of the amidoxime was then carried out with
25 commercially available acid chlorides in parallel
using a Bohdan MiniBlockTM reactor and TecanTM
liquid handler. The amidoxime bound resin was sus-
pened in DMF and treated with the selected acid chlo-
rides (5.6 equiv) in the presence of excess pyridine for
30 min. Each of the acid chlorides purchased was
employed directly without further puri®cation. Cyclo-
dehydration was then e€ected by treatment with TBAF
(2.2 equiv) in THF over 12 h under ambient conditions.
The use of a 2-fold excess of TBAF appears to be
necessary to achieve complete conversion to the oxa-
diazole. (In the case of acetyl substrate 4a, the use of
stoichiometric TBAF a€orded only partial cyclodehy-
dration to 5a even on extended reaction times.) Clea-
vage of the desired oxadiazoles from resin was carried
out using 95% aq TFA and the products isolated were
analyzed by LCMS after drying.
The general synthetic strategy employed in our study is
illustrated in Scheme 1. Argopore MB-CHO resin
(Argonaut Technologies, 0.9 mmol gÀ1) was reductively
The results of this preliminary survey are summarized in
Table 1. (With very limited exception the oxadiazole
products were directly isolated in 70% or greater purity
based on analytical HPLC with no major side reactions
apparent.) The methodology appears to be quite general
*Corresponding author. Tel.: +1-650-837-7063; fax: +1-650-837-
7303; e-mail: krice@exelixis.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00028-2

754
K. D. Rice, J. M. Nuss / Bioorg. Med. Chem. Lett. 11 (2001) 753±755
Scheme 1. Oxadiazole synthesis strategy. Reagents and conditions: (a) (MeO)3CH, PhCH2NH2; NaBH3CN, HOAc, THF; (b) 4-cyanobenzoyl
chloride, DMAP, DMF, pyridine; (c) 50% aq NH2OH, EtOH, re¯ux; (d) RCOCl, pyridine, DMF; (e) TBAF, THF; (f) 95% TFA; (g) for 6g only,
TBAF, THF.
Table 1. Results for oxadiazole 6 formation
(1.0 equiv, 5 min) a€ords the oxadiazole in 72% isolated
yield, the subsequent treatment of 6h in THF solution
with TBAF (2.2 equiv, 12 h) eciently gives nitrile 7.
Presumably, oxidation to the 5-benzoyl derivative 6
(R=C(O)Ph) followed by hydroxide mediated frag-
mentation of the resulting ketone a€ords oxadiazole 6
(R=H) and benzoic acid. Subsequent base promoted
oxadiazole fragmentation may then a€ord the nitrile.13
The observation of a transient species by LCMS
(M+14) and the detection of benzoic acid in the reac-
tion mixture provide support for this mechanistic
hypothesis.) An additional limitation was observed in
the case of 2,4,6-trimethylbenzoate 4p. For this sub-
strate, LCMS analysis after resin cleavage revealed that
ring closure remained incomplete under the reaction
conditions employed, a€ording a 3:1 ratio of 5-mesityl-
oxadiazole 6p and the corresponding O-acylamidoxime.
The relatively slow rate of ring closure may be due to
a steric e€ect associated with the aromatic ring 2,6-
substituents.
Substrate
R
% Yielda HPLC Mass
purityb detectedc
6a
6b
6c
6d
6e
6f
6g
6h
6i
Methyl
Cyclopropyl
Cyclobutyl
Cyclopentyl
Cyclohexyl
29
38
27
19
38
48
25
29
17
21
27
17
40
26
30
47
15
18
26
38
52
44
22
34
21
95
80
95
92
100
92
86
15
90
77
87
66
74
79
88
63
68
79
87
55
77
91
78
100
88
316.1
342.2
356.1
370.1
384.2
336.1
378.1
368.1
406.2
408.1
408.1
408.1
396.1
396.1
396.1
420.2
454.1
428.1
428.2
368.1
384.1
379.1
379.1
379.1
464.2
tert-Butyl
Phenyl
Phenylacetyl
Hydrocinnamyl
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
Mesityl
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
In summary, we have delineated some key aspects of the
generality of TBAF mediated cyclodehydration of
O-acylamidoximes to oxadiazoles on solid support.
With very limited exception, the methodology appears
to have a broad scope with respect to variation at the
oxadiazole 5-position. The relatively mild reaction con-
ditions employed suggests that the construction of
highly diverse combinatorial libraries comprised of 3,5-
disubstituted 1,2,4-oxadiazoles is practical. Studies
aimed at the further development of this methodology
and its application to the production of combinatorial
high-throughput screening libraries is in progress.
4-Biphenyl
1-Naphthyl
2-Naphthyl
2-Furyl
6u
6v
6w
6x
6y
Thiophene-2-yl
4-Pyridyl
3-Pyridyl
3,5-Dimethyloxazol-2-yl
1-Phenyl-5-propylpyrazol-4-yl
aPercent yield based on theoretical resin loading of 0.9 mmol/g.
bAnalytical HPLC was performed using a YMC-ODS 3Â50 mm
reverse phase column using a 2 min 10±90% methanol gradient in
0.1% TFA bu€ered water eluent with absorbance detection at 254 nm.
cLRMS (EI) values reported are either M+ or MNa+
.
Acknowledgements
The authors wish to thank Cindy Yu, Patrick Kearney,
and David Hager for their invaluable support as well as
Dr. Jim Leahy for helpful discussions.
with respect to substitution at the oxadiazole 5-position,
with a range of aliphatic, aromatic and heterocyclic
substituents being well tolerated. A surprising exception
was noted in the case of phenylacetyl substrate 4h. (In
this case, the oxadiazole 6h was detected as a minor
component (15% by HPLC) with the major product
being the corresponding nitrile 7.) (Although the pre-
paration of 6h in solution phase using TBAF in THF
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