Solid-phase synthesis of 1,3,4-oxadiazoline-5-thione derivatives from resin-bound acylhydrazines

Article abstract of DOI:10.1016/j.bmcl.2006.01.002

A new strategy for solid-phase synthesis of 2,5-disubstituted 1,3,4-oxadiazoles has been developed. The 1,3,4-oxadiazoline-5-thione derivatives were synthesized from resin-bound acylhydrazines in several steps providing 78-88% overall yields and excellent purity.

Full text of DOI:10.1016/j.bmcl.2006.01.002

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1828–1830
Solid-phase synthesis of 1,3,4-oxadiazoline-5-thione
derivatives from resin-bound acylhydrazines
*
*
Zhanxiang Liu, Jinlong Zhao and Xian Huang
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, People’s Republic of China
Received 19 October 2005; revised 16 December 2005; accepted 5 January 2006
Available online 25 January 2006
Abstract—A new strategy for solid-phase synthesis of 2,5-disubstituted 1,3,4-oxadiazoles has been developed. The 1,3,4-oxadiazo-
line-5-thione derivatives were synthesized from resin-bound acylhydrazines in several steps providing 78–88% overall yields and
excellent purity.
Ó 2006 Elsevier Ltd. All rights reserved.
The high-throughput synthesis and screening of targeted
and exploratory compound libraries has emerged as a
key objective within the pharmaceutical industry as a
means of identifying lead molecules with desirable bio-
ones possess sedative effects, antitubercular activity,
8
and antiphlogistic properties, also some derivatives
9
showed benzodiazepine activity. These have been of
interest to the medicinal chemist for many years. Substi-
tuted 1,3,4-oxadiazoles have been successfully prepared
1
logical activities. Solid-phase synthesis has been recog-
nized as a powerful and rapid method for the
preparation of a large number of structurally distinct
1
0
by traditional synthesis via acylhydrazine. Moreover,
all intermediates and products were obtained in required
purification by chromatography or recrystallization.
2
molecules. A spin-off associated with ‘rapid parallel
synthesis’ has been the construction of an impressive
database of solid-supported organic reactions, with re-
cent emphasis on the formation of small heterocyclic
N-Acylhydrazines are a versatile class of nitrogen-
substituted molecules with high degree of chemical reac-
tivity, used as precursors and intermediates of many
important organic molecules such as heterocycles, phar-
maceuticals, polymers, dyestuffs, and photographic
3
drug-like molecules on solid supports.
The major advantages of solid-phase organic synthesis
include simple separation and purification processes,
which can be easily automated, since reagents can be
used in excess, and impurities and by-products can be
removed by simple filtration and washing procedures.
Moreover, transferring traditional solution chemistry
to the solid-phase or exploring new synthetic routes on
solid support offers the opportunity for the development
of novel methodologies for construction of libraries of
small heterocyclic compounds.
1
1
12
products. Only few papers describe to prepare com-
binatorial libraries of heterocyclic compounds on solid
supports using this chemistry. To the best of our knowl-
edge, solid-phase synthesis of 1,3,4-oxadiazoline-5-thi-
one derivatives has not been reported up to now.
Herein, we describe solid-phase synthesis of 1,3,4-oxa-
diazoles from resin-bound acylhydrazines. We planned
to prepare polymer-supported hydrazide from the Mer-
rifield resin (Scheme 1). The Merrifield resin 1 was first
converted to the polymer-supported methyl ester resin
2 by reacting with excess methyl 4-hydroxy benzoate.
The methyl ester resin 2 was treated with hydrazine hy-
drate in HMPA at 90 °C for several hours to give the
corresponding hydrazide resin 3. In this step, HMPA
was essential to make the reaction finish completely.
The resin 3 thus prepared was then reacted with CS2/
KOH at reflux to afford the 2-mercapto-1,3,4-oxadia-
zole resin 4. Further reaction with NaOH and electro-
philic reagents (RX) gave the corresponding resin 5.
Release of the final 1,3,4-oxadiazoles 6 was effected after
Symmetrical and unsymmetrical 1,3,4-oxadiazoles have
been reported to be biologically versatile compounds
displaying a variety of biological effects, which include
4
5
6
antiinflammatory, antifungal, antiparasitic, and anti-
7
microbial activities. 2-Aryl-1,3,4-oxadiazoline-5-thi-
Keywords: Substituted 1,3,4-oxadiazoles; Solid-phase synthesis;
Acylhydrazines.
*
Corresponding authors. Tel./fax: +86 571 88807077; e-mail
addresses: liuzhanx@zju.edu.cn; huangx@mail.hz.zj.cn
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.002

Z. Liu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1828–1830
1829
NaO
CO Me
NH NH H O/HMPA
2
2
2
2
CH2Cl
O
2
CO Me
DMF
90˚C
2
1
O
1
. CS , KOH
2
N N
O
1. NaOH (aq.)
O
N NH2
SH
O
H
2. HCl
2
. RX
3
4
TFA/DCM
N
N
N N
O
O
S R
HO
S R
O
Scheme 1.
Table 1. Solid-phase synthesis of 1,3,4-oxadiazoline-5-thione
derivatives
diazoles on solid support. The use of resin-bound
acylhydrazines in the reaction benefits the solid-phase
synthetic route because it not only provides a short syn-
thetic route to the desired products but its chemical ver-
satility also adds to the diversity of the library. The
a
b
Entry
Product
R
X
Yield
%)
Purity
(%)
(
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
H
Cl
I
88
84
82
84
81
88
79
84
76
90
92
81
92
86
92
88
94
90
1,3,4-oxadiazoline-5-thione derivatives were synthesized
CH
Et
3
in several steps providing 78–88% overall yields and
excellent purity. The mild conditions were suitable for
application to the automated synthesis of diverse drug-
like molecules. Further work is in progress on the
solid-phase synthesis of heterocyclic compounds via
the resin-bound acylhydrazines.
Br
Br
Br
Cl
Cl
Br
Br
n-C
4
H
9
Allyl
PhCH
2
6g
6h
6i
4-NO -C
PhCOCH
2
6
H
4 2
CH
2
4-Me-PhCOCH
2
a
Yield of crude product based on the loading of acylhydrazine resin 3.
Determined by HPLC analysis.
b
Acknowledgment
cleavaged by treatment with 10% TFA in DCM. The
compounds 6 were obtained after simple filtering and
evaporating of the solvent. The products generally do
not require further purification and show good purity
by HPLC analysis.
We are grateful to the National Natural Science Foun-
dation of China (Project Nos. 20472072, 20332060) for
financial support.
Supplementary data
Table 1 summarizes the yields and purities of a number
of 1,3,4-oxadiazoline-5-thione derivatives that were
prepared using this methodology.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2006.01.002.
The successful formation of resin 2 was supported by a
comparative FTIR study of Merrifield resin 1 and a
sample of resin 2 (KBr pellets). In the IR spectrum of
resin 2, several characteristic signals were present which
confirmed the attachment of the methyl ester moiety to
References and notes
À1
1. (a) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem.
Res. 1996, 29, 144; (b) Li, J.; Murray, C. W.; Waszkowycz,
B.; Young, S. C. Drug Discov. Today 1998, 3, 105; (c)
Kenny, B. A.; Bushfield, M.; Parry-Smith, D. J.; Fogarty,
S.; Treherne, J. M. Prog. Drug Res. 1998, 51, 245; (d)
Golebiowski, A.; Klopfenstein, S. R.; Portlock, D. E.
Curr. Opin. Chem. Biol. 2001, 5, 273.
2. (a) Yoshida, J.; Itami, K. Chem. Rev. 2002, 102, 3693; (b)
Ganesan, A. Drug Discov. Today 2002, 7, 47; (c) Dorwald,
F. Z. Organic Synthesis on Solid Phase; Wiley-VCH:
Weinheim, 2000; (d) Obrecht, D.; Villalgordo, J. M. Solid-
Supported Combinatorial and Parallel Synthesis of Small-
Molecular-Weight Compound Libraries; Pergamon:
Oxford, 1998.
the resin. There was a strong band at 1714 cm , typical
for C@Os of the methyl esters. Also, the peak at
À1
1
of acylhydrazine resin 3 was shown by the disappeared
260 cm (CH -Cl) had disappeared. The formation
2
À1
strong carbonyl peak at 1714 cm . There was also a
weak peak at 1652 cm . When the acylhydrazine resin
was converted to the resin 4, the IR peak shifted to
À1
À1
1
612 cm . When the resin 5 was cleavaged by TFA/
DCM, the product 6 was obtained in good yield and
1
3,14
high purity. The resin 4 was treated with the base
(NaOH) and then reacted with a variety of electrophilic
reagents, such as alkyl halides, allyl bromide, benzyl ha-
lides, and phenylacyl bromide. All of these gave good
3
4
. Franzer, R. G. J. Comb. Chem. 2000, 2, 195.
. Omar, F. A.; Mahfouz, N. M.; Rahman, M. A. Eur. J.
Med. Chem. 1996, 31, 819.
1
5
results.
In summary, we have studied and developed a new strat-
egy for the preparation of 2,5-disubstituted 1,3,4-oxa-
5. (a) Goswami, B. N.; Kataky, J. C. S.; Baruah, J. N.; Nath,
S. C. J. Heterocycl. Chem. 1984, 21, 205; (b) Holla, B. S.;

1830
Z. Liu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1828–1830
Poojary, K. N.; Kalluraya, B.; Gowda, P. V. Indian J.
Heterocycl. Chem. 1996, 5, 273.
hydrazine hydrate in HMPA (1:1, 6 mL). The mixture was
stirred at 90 °C for 24 h. Filtered and washed with H O,
DMF, H O, EtOH, and CH Cl , the acylhydrazine resin 3
(loading = 1.59 mmol/g, based on N microanalysis) was
obtained (Caution! HMPA has relative toxicity).
2
6
7
. Omar, M. T. Arch. Pharm. Res. (Seoul) 1997, 20, 602.
. (a) Hamad, M. M.; Said, S. A.; El-Ekyabi, Y. M.
Monatsh. Chem. 1996, 127, 549; (b) Papakonstantinou,
G. S.; Marakos, P.; Tsantili, K. A.; Chytyroglon, L. A.
Pharmazie 1998, 53, 300.
2
2
2
14. General procedure for synthesis of 1,3,4-oxadiazoline-5-
thiones: To the mixture of the acylhydrazine resin 3 (0.5 g,
loading = 1.59 mmol/g), 5 mL of 2 M NaOH (aq), and
8
9
. Akbarzadeh, T.; Tabatabai, S. A.; Khoshnoud, M. J.;
Shafaghi, B.; Shafiee, A. Bioorg. Med. Chem. 2003, 11,
2
10 mL ethanol, CS (0.86 g, 10 mmol) was added. Then
7
69.
the mixture was heated at reflux for 8 h. After cooling, the
resin was filtered and 3 M HCl was added. The resin was
then washed with EtOH, CH Cl to remove contaminated
2 2
. Almasirad, A.; Tabatabai, S. A.; Faizi, M.; Kebriaee-
zadeh, A.; Mehrabi, N.; Dalvandi, A.; Shafiee, A. Bioorg.
Med. Chem. 2004, 14, 6057.
species, and then dried to offer the resin 4.
1
0. For 2-mercapto-1,3,4-oxadiazole synthesis, see: (a) Hog-
garth, E. J. Chem. Soc. 1952, 4811; (b) Lacasse, G.;
Muchowski, J. M. Can. J. Chem. 1972, 50, 3079; (c) Dodd,
D. S.; Shen, Z. Q.; Nishi, T.; Graber, N.; Bealls, D.; Fong,
M.; Ebert, T. Bioorg. Med. Chem. Lett. 1996, 6, 2693.
1. Licandro, E.; Perdicchia, D. Eur. J. Org. Chem. 2004, 665.
2. (a) Kobayashi, S.; Furuta, T.; Sugita, K.; Okitsu, O.;
Oyamada, H. Tetrahedron Lett. 1999, 40, 1341; (b)
Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron Lett.
To a suspension of resin 4 in EtOH (15 mL), 1 mL of 10%
NaOH was added. After being stirred for 30 min, RX
(4 mmol) was added. The mixture was stirred for another
4 h at room temperature. The resin 5 was collected on a
glass filter and washed completely with H O, EtOH, and
2
2 2 2 2
CH Cl . Resin 5 was well swollen in 4 mL CH Cl , and
1
1
0.8 mL TFA was added. The mixture was stirred at room
temperature for 1 h. The mixture was filtered and the resin
was washed with EtOH and CH Cl . The washings were
2
2
2
001, 42, 2583.
combined with the filtrate, concentrated to dryness to give
1
1
3. Procedure for the preparation of the resin-bound acylhy-
dride: To a stirred and cooled suspension of 50% NaH
the crude product 6. Compound 6a: mp 228–230 °C H
NMR (DMSO-d ) d 6.94 (d, 2H, J = 8 Hz), 7.86 (d, 2H,
6
1
3
(
0.48 g,10 mmol) in dry DMF (4 mL) was added dropwise
a solution of methyl 4-hydroxy benzoate (10 mmol, 1.52 g)
in 8 mL DMF under N atmosphere. The mixture was
J = 8 Hz), 10.51 (s, 1H); C NMR d 113.63, 116.76,
129.28, 160.80, 161.90, 167.50, MS m/z (relative intensity)
(EI 70ev) 194 (100), 134 (95), 119 (27), 107 (58), 79 (38)
2
À1
allowed to stand for 30 min at room temperature. Then
Merrifield resin (2 g, 1% cross-linked, 200–400 mesh,
loading = 1.95 meq Cl/g) was added and the mixture was
IR(KBr) tmax (cm ) 3396, 3172, 1612, 1514, 1490, 1354,
8 6 2 2
1167, 968, 838. Calcd for C H N O S, C, 49.47; H, 3.11;
N, 14.42; O, 16.48; S, 16.51. Found: C, 49.09; H, 3.26; N,
14.28.
stirred at rt for 24 h. After being washed with H O, DMF,
2
EtOH, and CH Cl , the methyl ester resin 2 was obtained.
2
The methyl ester resin 2 (2 g) was added to the solution of
15. The other analytical data of compounds 6b–6i were listed
in Supplementary material which is available online.
2