Mild and convenient one-pot synthesis of 2-amino-1,3,4-oxadiazoles promoted by trimethylsilyl isothiocyanate (TMSNCS)

Article abstract of DOI:10.1039/c3ra41044g

A mild, convenient, and efficient one-pot synthesis of amino-1,3,4- oxadiazoles is described. In situ preparation of various thiosemicarbazides by the reaction of different carboxylic acid hydrazides with trimethylsilyl isothiocyanate (TMSNCS), followed by cyclodesulfurization of thiosemicarbazides under basic conditions in the presence of I₂/KI resulted in 2-amino-1,3,4-oxadiazoles in high yields (79-94%).

Full text of DOI:10.1039/c3ra41044g

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Mild and convenient one-pot synthesis of 2-amino-
1,3,4-oxadiazoles promoted by trimethylsilyl
isothiocyanate (TMSNCS)3
Cite this: RSC Advances, 2013, 3, 7684
Received 2nd March 2013,
Accepted 14th March 2013
Dinneswara Reddy Guda, Hyeon Mo Cho and Myong Euy Lee*
DOI: 10.1039/c3ra41044g
www.rsc.org/advances
Table 1 Optimization of reaction conditions for the synthesis of 2-amino-5-
phenyl-1,3,4-oxadiazole(2a)
A mild, convenient, and efficient one-pot synthesis of amino-
1,3,4-oxadiazoles is described. In situ preparation of various
thiosemicarbazides by the reaction of different carboxylic acid
hydrazides with trimethylsilyl isothiocyanate (TMSNCS), followed
by cyclodesulfurization of thiosemicarbazides under basic condi-
tions in the presence of I2/KI resulted in 2-amino-1,3,4-oxadia-
zoles in high yields (79–94%).
Entry
Solvents
Time (h)a
Yield (%)b
Organosilicon compounds play an important role in organic
synthesis due to the ambient nature of silicon. Recently, the use of
organosilicon compounds as reagents and as intermediates in
organic synthesis has increased rapidly. It leads to an increasing
number of new methodologies that allow useful synthetic
transformations. Silicon compounds having functional groups,
such as silyl cyanides and silyl azides show considerable synthetic
applications in organic synthesis.1–4 Among various silicon
reagents, we particularly focused on trimethylsilyl isothiocyanate
(TMSNCS) due to its broad synthetic application. TMSNCS is a
useful reagent for thiocyanation or isothiocyanation of alkyl
halides,5 acetals,6 aldehydes,6 unsaturated compounds,7,8 aziri-
dines,9 oxiranes9 and aromatic hydrocarbons.10
1
2
3
4
5
Toluene
THF
H2O
MeOH
EtOH
14
12
8
7
4
15
39
68
73
94
a
b
Monitored by TLC until 1a was fully consumed. Isolated yield.
the aminooxadiazole analogues are currently undergoing clinical
evaluation for the treatment of diabetes.18 Due to these broad
applications, the chemistry of 2-amino-1,3,4-oxadiazoles has
Very recently we reported one-pot, convenient synthesis of
mercapto-1,2,4-triazoles using TMSNCS.11 As part of our continu-
ing studies on TMSNCS, we extended the synthetic utility of
trimethylsilyl isothiocyanate for the synthesis of other important
heterocycles. In this report we describe a new, simple, and
efficient one-pot synthesis of 2-amino-1,3,4-oxadiazoles from
carboxylic acid hydrazides using TMSNCS.
1,3,4-Oxadiazoles are a class of heterocycles which display a
wide range of biological activities.12 In particular, 2-amino-1,3,4-
oxadiazoles exhibit a wide variety of biological activities such as
anti-microbial,13 anti-inflammatory,14 anti-cancer,15 anti-convul-
sant16 and anti-mitotic17 activities. In addition to these, some of
Department of Chemistry & Medical Chemistry, College of Science and Technology,
Research & Education Center for Advanced Silicon Materials, Yonsei University,
Wonju, Gangwon-do 220-710, South Korea. E-mail: melgg@yonsei.ac.kr;
Fax: + 82-33-760-2182; Tel: + 82-33-760-2237
Scheme 1 Plausible mechanism for the formation of 2-amino-1,3,4-oxadiazoles
(2).
Electronic supplementary information (ESI) available: IR, 1H NMR, 13C NMR and
3
GC-MS spectra. See DOI: 10.1039/c3ra41044g
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Table 2 One-pot synthesis of 2-amino-1,3,4-thiadiazoles (2)
Table 2 (Continued)
Entry
12
Hydrazides
Products
Yield (%)
86
Entry
1
Hydrazides
Products
Yield (%)
94
13
88
2
91
evoked significant interest in the field of synthetic organic
chemistry. Hence there is a need to develop newer synthetic
routes for 2-amino-1,3,4-oxadiazoles.
3
4
92
91
There are various methods available in the literature for the
synthesis of 2-amino-1,3,4-oxadiazoles, which include cyclodehy-
dration of semicarbazide derivatives,19 cyclodesulfurization of
thiosemicarbazide derivatives20 and amination of oxadiazol-2-one
at the C2 carbon.21 However, there are limitations to these
methods, such as byproduct formation, handling of harsh and
toxic reagents, use of anhydrous solvents, chromatographic
purification, etc.
In contrast, we report herein a highly efficient one-step
protocol to prepare 2-amino-1,3,4-oxadiazoles from the reaction
of commercially available hydrazides and TMSNCS in EtOH under
basic conditions in the presence of I2/KI at 70 uC. Importantly, the
procedure does not require an anhydrous solvent, inert gas
atmosphere, and any chromatographic purification.
5
6
88
86
In our previous report we optimized the reaction conditions for
the in situ preparation of thiosemicarbazides.11 Based on our
previous report we synthesized 2-amino-1,3,4-oxadiazoles by the
one-pot method without any isolation of thiosemicarbazides.
Initially benzohydrazide 1a (1.0 mmol), TMSNCS (1.0 mmol) and
5% KI/I2 were selected for a model reaction and the effects of
different solvents and reaction temperatures were investigated.
The results are summarized in Table 1. EtOH was the best solvent
among various solvents such as toluene, THF, H2O, and MeOH.
Benzohydrazide 1a (1.0 mmol) and TMSNCS (1.0 mmol) in EtOH
(10 mL) were refluxed for about 4 h, and then we added 5N NaOH
and 5% I2/KI solution to the reaction mixture and the solution was
refluxed for 2 h. It was then cooled and poured into crushed ice to
obtain the precipitated product, 2-amino-5-phenyl-1,3,4-oxadizole
(2a) with a yield of 94%.
The plausible mechanism for the formation of 2-amino-5-aryl-
1,3,4-oxadizole (2) is shown in Scheme 1. The nucleophilic
cleavage of the Si–N bond in TMSNCS takes place in the presence
of EtOH and forms a highly reactive isothiocyanic acid inter-
mediate. Carboxylic acid hydrazides (1) immediately undergo
nucleophilic addition to isothiocyanic acid, leading to the
corresponding stable thiosemicarbazides. Iodine then catalyzes
their cyclodesulfurization20,22 to form 2-amino-5-aryl-1,3,4-oxadia-
zole (2).
7
8
87
84
9
83
79
81
10
11
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Having these preliminary observations in hand, we wished to
extend our methodology to a variety of carboxylic acid hydrazides.
The reactions of 1a–m with TMSNCS in the presence of I2/KI gave
the 2-amino-1,3,4-oxadiazole (2a–m)23 with high yields (Table 2).
As shown in Table 2, compound 2a (entry 1) was obtained in the
highest yield compared to that of the electron-rich and the
electron-poor aryl substituted derivatives 2b–i (entries 2–9). As we
observed, hydrazides carrying an electron-withdrawing group or
an electron-donating group reacted successfully. In particular,
4-substituted derivatives 1b–e (entries 2–5) reacted more efficiently
than the corresponding 2-substituted regioisomers 1f–i (entries 6–
9), possibly because of the steric hindrance of the ortho
substituent. To demonstrate the generality of our methodology,
we extended our investigation to substrates bearing alkyl and
hetero-aromatic groups. With heteroaryl acid hydrazides (entries
12 and 13), yields were similar to those with aromatic derivatives,
but with alkyl acid hydrazides (entries 10 and 11), yields were
slightly lower than those of the aromatic and heteroaromatic acid
hydrazides.
Conclusions
In summary, the current protocol is a simple and straightforward
route for the synthesis of 2-amino-1,3,4-oxadiazoles. Various
aliphatic, aromatic, and heteroaromatic 2-amino-1,3,4-oxadiazoles
were efficiently synthesized using TMSNCS and carboxylic acid
hydrazides. The main advantage of this method is that the
experimental procedure is operationally simple, and an anhydrous
solvent, an inert gas atmosphere and chromatographic purifica-
tion are not required. The use of harsh reagents was also avoided.
Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2010-0024877).
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dropwise with stirring until the colour of iodine persisted at
room temperature. The reaction mixture was refluxed for an
additional 1–2 h, cooled and poured into ice-cold water. The
resultant solid was filtered on a Buchner funnel and dried.
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products.
23 Typical experimental procedure for synthesis of 2-amino-5-sub-
stituted-1,3,4-oxadiazole (2a–m): A mixture of acid hydrazide (1.0
mmol) and trimethylsilyl isothiocyanate (1.0 mmol) and
ethanol (10 ml) was refluxed for 2–4 h and then 1.0 ml of 5N
NaOH was added, resulting in the formation of a clear solution.
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