Efficient one-pot preparation of 5-substituted-2-amino-1,3,4-oxadiazoles using resin-bound reagents

Article abstract of DOI:10.1016/j.tetlet.2004.02.119

A robust one-pot solution-phase synthesis of 2-amino-1,3,4-oxadiazoles directly from acylhydrazines and isothiocyanates is described. Commercially-available polymer-supported reagents help facilitate both cyclization and purification. This convenient meth

Full text of DOI:10.1016/j.tetlet.2004.02.119

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3257–3260
Efficient one-pot preparation of 5-substituted-2-amino-1,3,4-
oxadiazoles using resin-bound reagents
Frank T. Coppo, Karen A. Evans,* Todd L. Graybill and George Burton
GlaxoSmithKline Pharmaceuticals, Discovery Research, 1250 South Collegeville Road, PO Box 5089, Collegeville,
PA 19426-0989, USA
Received 29 October 2003; accepted 25 February 2004
Abstract—A robust one-pot solution-phase synthesis of 2-amino-1,3,4-oxadiazoles directly from acylhydrazines and isothiocyanates
is described. Commercially-available polymer-supported reagents help facilitate both cyclization and purification. This convenient
method benefits from its broad applicability, ease and safety of reagent handling, simple product isolation, and the ability to
perform multiple reactions in parallel fashion without need for purification. The details and scope of this reaction strategy are
presented herein.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
as mercury(II) acetate (Hg(OAc)2) or yellow mercury(II)
oxide (HgO).7 These latter methods require a full
equivalent of Hg(II) and produce undesirable mercury
byproducts that must then be removed and properly
disposed of after the reaction is completed. Moreover,
these methods are usually carried out in two discrete
synthetic steps. In the first step, the reaction of the
hydrazide 2 (Scheme 1) with an isothiocyanate (R2NCS)
provides the acylthiosemicarbazide 3, which is typically
isolated from the reaction mixture and purified by
recrystallization. In the second step, the cyclization is
accomplished using one of the aforementioned condi-
tions and the oxadiazole product 1 is frequently isolated
and purified by recrystallization.
Many 1,3,4-oxadiazoles are reported in the literature to
have a broad spectrum of biological activity including
antimicrobial,1 antifungal,2 anti-inflammatory,3 and
hypotensive activity.4 During hit to lead efforts follow-
ing a recent high throughput screening campaign, we
initiated an SAR program that required the synthesis of
a series of 5-substituted-2-amino-oxadiazoles 1.
R1
N
N
O
N
H
R2
These solution-phase methods, while successful, were
deemed not readily amenable to high throughput syn-
thesis, and thus did not meet our needs. A solution-
phase dehydrative synthesis from 1,2-diacylhydrazines8
and several solid-phase methods were also considered.9
1
Our objective was to prepare an array of 192(12
R1 ꢀ 16 R2) 5-substituted-2-amino-oxadiazole ana-
logues by rapid parallel synthesis. Literature syntheses
of these oxadiazoles5 include cyclodesulfurization of
acylthiosemicarbazide derivatives in solution using I2/
NaOH or 1,3-dicyclohexylcarbodiimide (DCC),6 as well
Here we report our efficient one-pot solution-phase
preparation of 5-substituted-2-amino-1,3,4-oxadiazoles
1 directly from the acyl hydrazines 2 via commercially-
available polymer-supported reagents. The key advan-
tages of this method are the ability to perform multiple
reactions with multiple substrates in parallel fashion,
simplicity of work-up (simple filtration), ease and safety
of reagent handling, and elimination of the need for
purification as the products are typically obtained in
high purity and good yields.
Keywords: Oxadiazole; 2-Amino-1,3,4-oxadiazole; 1,3,4-Oxadiazole;
Carbodiimide; Acylhydrazine; Acylthiosemicarbazide; Parallel synthe-
sis; Solid-supported reagents.
* Corresponding author. Tel.: +1-610-917-7764; fax: +1-610-917-4206;
e-mail: karen_a_evans@gsk.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.119

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F. T. Coppo et al. / Tetrahedron Letters 45 (2004) 3257–3260
R1
H
N
N
H
N
R1
N
R1
NH
R2NCS
Cyclization
NH2
O
O
R2
O
S
N
N
R2
H
H
2
3
1
Scheme 1. Typical two-step solution-phase synthesis of oxadiazoles 1.
2. Results and discussion
to accommodate swelling of the resin. The vessels were
then heated at 80 °C for 60 h. P-Propylamine (0.2equiv)
and PS-bemp (0.2equiv) were added and the resin sus-
pension was shaken an additional 17 h before collection
of the desired product.14 After collection of the filtrate
and one wash of the resin (5 mL) with tetrahydrofuran
(THF), final evaporation typically provided the
oxadiazole 1 as a white solid in excellent purity15 (as
characterized by LCMS and 1H NMR)16 and good
yield.17 Representative results are shown in Table 1.
Most of these products have not previously been
In order to prepare these compounds by rapid parallel
synthesis, we needed a clean and efficient method to
form the oxadiazoles, preferably directly from hydraz-
ides 2 without isolation of 3. Since multistep sequences
can often be facilitated by use of resin-bound reagents,10
and since the synthesis of 1,3,4-oxadiazoles via reaction
of acylthiosemicarbazides 3 with DCC was known, it
was logical to extend this method by using a resin-bound
carbodiimide for the reaction with the additional
advantage of a simplified work-up (Fig. 1).
1
reported in the literature. A typical H NMR spectrum
of isolated product is shown in Figure 2for compound
1c.
The procedure described here was performed either in
glass vials or fritted polypropylene or Teflonâ reaction
tubes.11 Hydrazides 2a–h were prepared by reaction of
the corresponding ester with hydrazine12 or purchased
commercially (2i–k). Typically, 1.1 equiv of isothio-
cyanate were added neat to a solution of the hydrazide 2
(0.2mmol) in 3 mL DMF. The resulting solution was
allowed to mix at room temperature (rt) overnight
(20 h). PS-Carbodiimide13 (5 equiv) was added directly
to the reaction solution with an additional 3 mL DMF
It is important to note that the one-pot conditions
described herein (with cyclization temperature 80 °C,
60 h) represent a robust generic protocol that makes
possible the synthesis of an array of 2-amino-1,3,4-
oxadiazoles of diverse structure. However, we also
determined that for many substrates, shorter reaction
times, and milder cyclization conditions provide very
comparable yields and purities. For example, cyclization
tBuN
N
NEt2
N
P
CH3
N
C
P
NH2
Si
O
N
P
PS-Carbodiimide
P-Propylamine
PS-Bemp
Figure 1. Structures of resin-bound reagents.
Table 1. Representative results using the described methods
d
Compound
R1
R2% Yield
LCMS puritye
1aa
1ba
1ca
1da
1eb
1fb
1gb
1hb
1i
2-F, 6-Cl-PhCH2
3,4-Di-Cl–PhCH2
3-Pyridyl–CH2
3,4-OCH2OPhCH2
2-F, 6-Cl-PhCH2
3,4-Di-Cl–PhCH2
3-Pyridyl–CH2
3,4-OCH2OPhCH2
Ph
Ph
Ph
74
75
90
96
Ph
Ph
82100
73
69
86
100
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Me
72100
64
73
100
100
100
91
71
76
1j
1kc
Ph
Ph
Isobutyl
Ph
67
96
a Alternative method A: Step 2, rt, 20 h.
b Alternative method B: Step 2, 80 °C, 20 h.
c Alternative method C: Step 2, rt, 40 h.
d Isolated product yield.
e Identity and purity determined by LCMS using UV 214 detection.

F. T. Coppo et al. / Tetrahedron Letters 45 (2004) 3257–3260
3259
the acylhydrazines 2 via commercially-available poly-
mer-supported reagents has not been reported, though
the use of solid-supported reagents and scavengers in
multistep syntheses is well known. This convenient and
useful method benefits from its broad applicability, ease
and safety of reagent handling, simple product isolation,
and the ability to perform multiple reactions in parallel
fashion without need for purification.
Acknowledgements
The authors thank Walter Johnson for his assistance
with the LCMS spectra and Victoria Magaard for her
assistance with array processing.
References and notes
1. (a) Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med.
Chem. 2000, 35, 267–271; (b) Cesur, N.; Birteksoz, S.;
Otuk, G. Acta Pharm. Turcica 2002, 44, 23–41; (c) Laddi,
U. V.; Desai, S. R.; Bennur, R. S.; Bennur, S. C. Ind. J.
Heterocycl. Chem. 2002, 11, 319–322.
Figure 2. 1H NMR (400 MHz, DMSO-d6) of representative oxadiazole
1c.
2. (a) Zou, X.; Zhang, Z.; Jin, G. J. Chem. Res., Synopses
2002, 228–230; (b) Zou, X.-J.; Lai, L.-H.; Jin, G.-Y.;
Zhang, Z.-X. J. Agric. Food Chem. 2002, 50, 3757–3760.
3. Palaska, E.; Sahin, G.; Kelicen, P.; Durlu, N. T.; Altinok,
G. Farmaco 2002, 57, 101–107.
R1
N
1. R2-NCS, 1.1 eq, rt, 20 h,
rt, DMF
H
R1
N
N
NH2
2. PS-Carbodiimide, 5 eq,
O
°
60 h, 80 C
4. Tyagi, M.; Kumar, A. Oriental J. Chem. 2002, 18, 125–
130.
O
3. P-Propylamine, 0.2 eq
PS-Bemp, 0.2 eq
N
H
R2
5. The chemistry of 1,3,4-oxadiazoles has been reviewed: (a)
Hetzheim, A.; Moeckel, K. Adv. Heterocycl. Chem. 1966,
7, 183–224; (b) Hill, J. In Comprehensive Heterocyclic
Chemistry; Potts, K. T., Ed.; Pergamon: Oxford, 1984;
Vol. 6, pp 427–446.
2
1
Scheme 2. Improved one-pot solution-phase preparation of 2-amino-
oxadiazoles 1.
6. Examples: I2: (a) Gani, R. S.; Pujar, S. R.; Gadaginamath,
G. S. Ind. J. Heterocycl. Chem. 2002, 12, 25–28; (b)
Golovlyova, S. M.; Moskvichev, Y. A.; Alov, E. M.;
Kobylinsky, D. B.; Ermolaeva, V. V. Chem. Heterocycl.
Compd. 2001, 37, 1102–1106; (c) Liu, F. M.; Wang, B. L.;
Zhang, Z. F. Youji Huaxue 2001, 21, 1126–1131; (d) DCC
or I2: Omar, F. A.; Mahfouz, N. M.; Rahman, M. A. Eur.
J. Med. Chem. 1996, 31, 819–825; (e) DCC: AboulWafa,
O. M.; Omar, A. M. M. E. Sulfur Lett. 1992, 14, 181–188.
7. Hg(OAc)2: (a) Zou, X.; Zhang, Z.; Jin, G. J. Chem. Res.,
Synopses 2002, 228–230; (b) Hg(OAc)2 with microwave
irradiation: Wang, X.; Li, Z.; Wei, B.; Yang, J. Synth.
Commun. 2002, 32, 1097–1103; (c) HgO: Faidallah, H. M.;
Sharshira, E. M.; Basaif, S. A.; A-Ba-Oum, A. E. Phos.
Sulf. Sil. Rel. Elem. 2002, 177, 67–79.
to the oxadiazole is accomplished at room temperature
for analogues derived from aryl isothiocyanates (i.e., 1a–
d,k). These alternative conditions are provided in the
footnotes of Table 1.
This simple one-pot method (Scheme 2) can be applied
using simple glass or plastic reaction vials on a variety of
parallel synthetic platforms including the Robbins Flex–
Cheme system, Mettler–Toledo Bohdan MiniBlockse,
and the Argonaut Queste 210. In this case, the SAR
array of approximately 200 oxadiazoles was successfully
prepared using polypropylene reaction tubes in con-
junction with the MiniBlocke synthesis system.
8. (a) Brain, C. T.; Brunton, S. A. Synlett 2001, 382–384; (b)
Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J.
Tetrahedron Lett. 1999, 40, 3275–3278.
9. (a) Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron
Lett. 2001, 42, 2583–2586; (b) Brown, B. J.; Clemens, I. R.;
Neesom, J. K. Synlett 2000, 131–133.
3. Conclusion
10. For a review of multistep synthesis using solid-supported
reagents and scavengers, see: (a) Ley, S. V.; Baxendale, I.
R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbot-
tom, D. A.; Nesi, M.; Scott, J. S.; Storer, I.; Taylor, S. J.
J. Chem. Soc., Prekin Trans. 1 2000, 3815–4195; (b) For a
recent example of multistep syntheses faciliated by resin-
bound reagents, see Adams, G. L.; Graybill, T. L.;
Sanchez, R. M.; Magaard, V. W.; Burton, G.; Rivero,
R. A. Tetrahedron Lett. 2003, 44, 5041–5045.
In summary, we report a robust one-pot solution-phase
synthesis of 2-amino-1,3,4-oxadiazoles directly from
acylhydrazines and isothiocyanates. Commercially-
available polymer-supported reagents help facilitate
both cyclization and purification. To our knowledge,
an efficient one-pot solution-phase preparation of
5-substituted-2-amino-1,3,4-oxadiazoles 1 directly from

3260
F. T. Coppo et al. / Tetrahedron Letters 45 (2004) 3257–3260
11. Reagents were obtained from either the Aldrich Chemical
Co., Lancaster Synthesis, or Alfa/Aesar Organics and used
without further purification.
12. Marino, J. P.; Thompson, S. K.; Veber, D. F. SmithKline
Beecham Corp. WO 02/078696 A1 (2002).
13. PS-Carbodiimide (Cat. no 800371, 1.1 mmol/g) was
obtained from Argonaut Technologies, 1101 Chess Drive,
Foster City, CA 94404.
14. 3-Aminopropyl functionalized silica gel (Aldrich,
1.0 mmol/g) was added to scavenge the excess isothio-
cyanate from the first step. PS-Bemp (Fluka, Cat. no
20026, 2.2 mmol/g) was added to scavenge any unreacted
acylthiosemicarbazide, though this was typically not
observed by LCMS.
10–90% ACN/H2O containing 0.02% TFA (3.6 min gra-
dient) and monitored by a UV detector operating at
214 nm and by a SEDEX 75 evaporative light scattering
detector (ELSD) operating at 42 °C. LCMS [M+H] signals
were consistent with expected MW for all reported
products.
16. Physical data for 1c: 1H NMR (d6-DMSO, 400 MHz): d
10.38 (1H, s, NH), 8.59 (1H, d, J ¼ 2:0 Hz), 8.51 (1H, dd,
J ¼ 4:8, 1.6 Hz), 7.76 (1H, dt, J ¼ 8:0, 2.0 Hz), 7.52 (2H,
dt, J ¼ 8:0, 2.0 Hz), 7.40 (1H, ddd, J ¼ 8:0, 4.8, 0.8 Hz),
7.32(2H, ddd,
J ¼ 8:0, 2.0, 0.8 Hz), 6.97 (1H, app dt,
J ¼ 7:2, 0.8 Hz), 4.24 (2H, s). LCMS [M + H] ¼ 253.2, 1.28
in., 100% purity (UV 214 nm).
17. All compounds reported herein were characterized by H
1
15. Purity data reported here was determined by a C18 reverse
phase HPLC column [Keystone Aquasil (1 ꢀ 40 mm)] in
NMR to confirm the purity assessment of the LCMS
data.