Synthesis of 2-amino-5-substituted-1,3,4-oxadiazoles using 1,3-dibromo-5,5-dimethylhydantoin as oxidant

Article abstract of DOI:10.1016/j.tetlet.2006.05.033

A scalable synthesis of 5-substituted-2-amino-1,3,4-oxadiazoles via oxidation of a thiosemicarbazide precursor is described. The thiosemicarbazide intermediates are easily accessed from the corresponding acid chlorides. Oxidative cyclization using 1,3-dibromo-5,5-dimethylhydantoin as the primary oxidant, in the presence of potassium iodide, gives a variety of oxadiazoles in good yields. This methodology utilizes a commercially inexpensive and easily handled oxidant.

Full text of DOI:10.1016/j.tetlet.2006.05.033

Tetrahedron Letters 47 (2006) 4889–4891
Synthesis of 2-amino-5-substituted-1,3,4-oxadiazoles using
1,3-dibromo-5,5-dimethylhydantoin as oxidant
Nelo R. Rivera,* Jaume Balsells and Karl B. Hansen
Department of Process Research, Merck Research Laboratories, Merck & Co., PO Box 2000, Rahway, NJ 07065, United States
Received 22 November 2005; revised 4 May 2006; accepted 8 May 2006
Abstract—A scalable synthesis of 5-substituted-2-amino-1,3,4-oxadiazoles via oxidation of a thiosemicarbazide precursor is
described. The thiosemicarbazide intermediates are easily accessed from the corresponding acid chlorides. Oxidative cyclization
using 1,3-dibromo-5,5-dimethylhydantoin as the primary oxidant, in the presence of potassium iodide, gives a variety of oxadiazoles
in good yields. This methodology utilizes a commercially inexpensive and easily handled oxidant.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Molecules containing a 1,3,4-oxadiazole core have been
shown to have a broad range of important biological
activities including antibacterial,1 antimicrobial,2 hypo-
tensive,3 insecticidal,4 herbicidal, and antifungal5
properties. As part of an ongoing drug development
program, we required an efficient and scalable
method to prepare 2-amino-oxadiazole containing
molecules.
Some of the methodologies reported in the literature to
prepare this type of compounds are summarized in
Scheme 1. Approaches 1 and 2 involve the formation
N
O
Br
H2N
N
H
S
O
N
H2N
N
H
N
H
HN
N
O
1
N
5
4
H2N
N
H
N
2
O
H2N
N
N
O
H
S
O
H2N
N
3
N
H
H2N
N
N
H
O
Scheme 1. Retrosynthetic approaches to amino-oxadiazoles.
*
Corresponding author. Tel.: +1 732 594 0355; fax: +1 732 594 6703; e-mail: nelo_rivera@merck.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.033

4890
N. R. Rivera et al. / Tetrahedron Letters 47 (2006) 4889–4891
Table 1. Synthesis of thiosemicarbazides13
of the desired heterocycle via a hydrazide intermediate.6
The preparation of these intermediates requires the use
of hazardous hydrazine, which made these approaches
undesirable for large scale synthesis. The dehydration
of diacylhydrazides7 (approach 3) has also been used
to prepare the desired heterocycle, although it requires
harsh conditions. Finally, acylthiosemicarbazide inter-
mediates have been used in different ways to generate
2-amino-1,3,4-oxadiazoles. Sulfur methylation of an
acylthiosemicarbazide induces cyclization (approach
4).8 However, this strategy involves the use of toxic
methylating reagents and generates volatile thiols as a
byproduct of the reaction. Acylthiosemicarbazides can
be cyclized to the corresponding oxadiazoles via carbo-
diimide mediated cyclizations9 but there are issues of
either cost or rejection of urea byproducts associated
with this approach. Alternatively, acylthiosemicarb-
azides can be cyclized by oxidation with iodine10 at
elevated temperatures (approach 5).
S
O
O
H
N
H2N
NHNH2
NH2
Ar
Cl
Ar
N
H
THF, rt
S
1
2
2
Ar
Ph
4-Cl–Ph
Yield of 2 (%)
a
b
c
88
92
92
4-OMe–Ph
O
d
e
f
68
85
72
Table 2. Oxidant screen
From both a safety and an economical standpoint, we
were interested in the oxidative cyclization of acylthio-
semicarbazides to prepare the desired 2-amino-1,3,4-
oxadiazole. However, there are some liabilities associ-
ated with handling iodine on large scale including its
high cost, the stability of iodine solutions, and its corro-
sive and lachrymatory properties. Thus, we set out to
find an alternative oxidant that was economical and
could be safely handled in large scale. Herein we report
the use of 1,3-dibromo-5,5-dimethylhydantoin as the
primary oxidant, in the presence of potassium iodide,
for the oxidative cyclization of acylthiosemicarbazides.
O
H
O
[O]
Ph
N
NH2
NH2
Ph
N
NaOH
H
N
N
S
Entry
Oxidant
Additive
Assay yield (%)
1
2
3
4
5
6
7
8
9
mCPBA
H2O2
Bleach
Bleach
Bleach
Bleach
NBS
Hydantoin
Hydantoin
None
None
None
Iodine
TEMPO
KI
None
None
KI
4
4
23
27
24
18
59
63
75
In addition to exploring various oxidative cyclization
methods, an expedient synthesis of the acylthiosemicarb-
azide intermediate would be desirable as well. Tradi-
tional methods for preparing this intermediate include
reacting acylhydrazines with isothiocyanates or potas-
sium thiocyanates.11 We found that treating the appro-
priate acid chloride with thiosemicarbazide in THF
was a straightforward method to prepare the desired
acylthiosemicarbazide intermediate in good to excellent
yields (Table 1).12
is enough to drive the reaction to completion. The addi-
tion of catalytic amounts of KI to the reaction, further
boosted the yields obtained.
After optimization of the reaction conditions, we found
0.75 equiv of 1,3-dibromo-5,5-dimethylhydantoin in the
presence of 0.3 equiv of potassium iodide, with NaOH
as base and isopropyl alcohol/acetonitrile as solvent,
effectively gives the desired 5-substituted-2-amino-
oxadiazole in high yield and purity. Presumably, iodine
is generated in situ as indicated by the brown color
formed during the course of addition of 1,3-dibromo-
5,5-dimethylhydantoin solution to the reaction mixture
containing substrate and potassium iodide. Alcoholic
solvents work well for this reaction, although some
decomposition of the acylthiosemicarbazide by trans-
esterification was observed when ethanol or methanol
were used. This side reaction was completely suppressed
when isopropyl alcohol was used. Organic bases such as
triethylamine or DBU may be used in the reaction.
Using the optimized conditions, a number of 2-aminoxa-
diazoles were prepared in good yields as shown in
Table 3. Various aryl substrates are tolerated as well
as alkyl, alkenyl, and heterocyclic compounds.
Although 1,3-dibromo-5,5-dimethylhydantoin has been
used as a brominating reagent,14 no brominated side
products were found under these conditions.
With the acylthiosemicarbazide intermediate in hand, a
number of oxidants were examined to promote the cycli-
zation (Table 2). Oxidants such as mCPBA, H2O2 and
bleach (entries 1–3) gave some product but in low yields.
Addition of catalytic amounts of iodine, TEMPO, or KI
with bleach as terminal oxidant did not improve the
yields in any appreciable amounts (entries 4–6). N-
Bromosuccinimide gave moderate yields that could
probably be improved with optimization but the succin-
imide byproduct was difficult to remove completely in
the downstream chemistry.
1,3-Dibromo-5,5-dimethylhydantoin (entry 8) also
proved to be a competent oxidant in this reaction.
Unlike NBS however, the resulting dimethylhydantoin
byproduct is highly water soluble and can be easily
rejected during aqueous work-up. Furthermore, since
both bromine atoms on the hydantoin are utilized for
the oxidation, a substoichiometric amount of hydantoin

N. R. Rivera et al. / Tetrahedron Letters 47 (2006) 4889–4891
4891
Table 3. Synthesis of amino-oxadiazoles15
5. Zou, X.-J.; Lai, L.-H.; Jin, G.-Y.; Zhang, Z.-X. J. Agric.
Food Chem. 2002, 50, 3757–3760.
O
H
O
NH2
Ar
6. For example: (a) Mullican, M. D.; Wilson, M. W.;
Connor, D. T.; Kostlan, C. R.; Schrier, D. J.; Dyer, R.
D. J. Med. Chem. 1993, 36, 1090–1099; (b) Wu, Y.-Q.;
Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S.
J. Heterocycl. Chem. 2003, 40, 191–193.
7. For example: (a) Fulop, F.; Semega, E.; Dombi, G.;
Bernath, G. J. Heterocycl. Chem. 1990, 27, 951–955; (b)
Gehlen, H.; Mockel, K. Justus Liebigs Ann. Chem. 1965,
685, 176–180; (c) Borg, S.; Estenne-Bouhtou, G.; Luth-
man, K.; Csoregh, I.; Hesselink, W.; Hacksell, U. J. Org.
Chem. 1995, 60, 3112–3120.
N
NH2
Ar
N
N
N
H
S
3
2
3
Ar
Ph
Yield of 3a (%)
a
b
c
75
88
97
4-Cl–Ph
4-OMe–Ph
O
d
e
f
83
8. Fulop, F.; Semega, E.; Dombi, G.; Bernath, G. J.
Heterocycl. Chem. 1990, 27, 951–955.
53b
74
9. For example: (a) Kilburn, J. P.; Lau, J.; Jones, R. C. F.
Tetrahedron Lett. 2001, 42, 2583–2586; (b) Baxendale, I.
R.; Ley, S. V.; Martinelli, M. Tetrahedron 2005, 61, 5323–
5349; (c) Coppo, F. T.; Evans, K. A.; Graybill, T. L.;
Burton, G. Tetrahedron Lett. 2004, 45, 3257–3260.
10. For example: (a) Zhang, R.; Qian, X.; Li, Z. J. Fluorine
Chem. 1999, 93, 39–43; (b) Gani, R. S.; Pujar, S. R.;
Gadaginamath, G. S. Indian J. Heterocycl. Chem. 2002,
12, 25–28.
Conditions: 5 N NaOH, KI, H2O, iPrOH, 1,3-dibromo-5,5-di-
methylhydantoin, ACN 5 ꢁC.
a Assay yields reported as determined by HPLC analysis.
b 15% of starting material was recovered.
11. For example: (a) Coppo, F. T.; Evans, K. A.; Graybill, T.
L.; Burton, G. Tetrahedron Lett. 2004, 45, 3257–3260; (b)
Zhang, R.; Qian, X.; Li, Z. J. Fluorine Chem. 1999, 93, 39–
43.
12. Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan,
C. R.; Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1993, 36,
1090–1099.
13. Preparation of benzoyl thiosemicarbazide (2a). Benzoyl
chloride 1a (5.0 g, 35.6 mmol) was dissolved in THF
(75 mL) and the solution was cooled to 15 ꢁC. Thiosemi-
carbazide (7.1 g, 77.9 mol) was then added portionwise
and the reaction mixture was aged at room temperature
for several hours. After the reaction was complete, the
solution was quenched with aqueous NaHCO3 (50 mL)
and extracted with EtOAc (100 mL). The organic layer
was then washed with aqueous NaHCO3 (50 mL), then
brine (50 mL), dried over MgSO4 and concentrated under
vacuum. The resulting solid was slurried in H2O (50 mL)
at room temperature, filtered and dried to give 2a (6.08 g,
88% isolated yield).
A yellow solid was obtained as a byproduct of the reac-
tions and determined to be elemental sulfur by analysis.
The formation of this byproduct seems to indicate that
under basic conditions and in the presence of an oxi-
dant, the reaction proceeds via formation of a dithiane
species. This would then be followed by cyclization to
form the oxadiazole ring with simultaneous extrusion
of sulfur.
In summary, we presented an expedient route to various
2-amino-5-substituted-1,3,4-oxadiazoles. The acylthio-
semicarbazide intermediate is accessed easily by reacting
an acid chloride with thiosemicarbazide. Cyclization
via desulfurization using 1,3-dibromo-5,5-dimethylhyd-
antoin as the primary oxidant, in the presence of potas-
sium iodide, gives a variety of oxadiazoles in good
yields. The main advantage to this approach is that
the reagents used are commercially inexpensive and safe
to handle. This methodology offers a safe alternative to
current oxidative cyclization methodologies, and is
especially applicable for large scale synthesis where the
use of other oxidants may be prohibitive.
14. For example: (a) Chassaing, C.; Haudrechy, A.; Langlois,
Y. Tetrahedron Lett. 1997, 38, 4415–4416; (b) Ishizumi,
K.; Ohashi, N.; Tanno, N. J. Org. Chem. 1987, 52, 4477–
4485.
15. Preparation of 2-amino-5-phenyl-1,3,4-oxadiazole (3a).
Benzoyl thiosemicarbazide 2a (1.0 g, 5.12 mmol) was
taken up in iPrOH (8 mL) to which was added a solution
of KI (0.255 g, 1.54 mmol) in H2O (2 mL) at room
temperature. The solution was then cooled to 5 ꢁC and
5 N NaOH (1.54 mL, 7.7 mmol) was added to give a clear
homogeneous solution. A solution of 1,3-dibromo-5,5-
dimethylhydantoin (1.1 g, 3.85 mmol) in acetonitrile
(10 mL) was then added to the reaction mixture over 1 h
while maintaining the temperature under 10 ꢁC. After the
addition, the mixture was aged for 1 h at this temperature
and the reaction was quenched with aq NaHSO3
(0.25 mL). EtOAc (25 mL) was then added to the slurry,
the solids filtered and washed with EtOAc (10 mL). The
filtrate was washed twice with NaHCO3 (2 · 15 mL) and
once with brine (15 mL). The organic extracts were dried
over MgSO4, filtered and concentrated. The resulting solid
was slurried in H2O (10 mL), filtered and slurry washed
with EtOAc (2 · 2 mL) to give 3a (507 mg, 62% isolated
yield).
References and notes
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