RSC Advances
Communication
Acknowledgements
Table 2 (Continued)
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2010-0024877).
Entry Hydrazides
11
Products
Yield (%) Ref.
72
38
References
12
13
83
39
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85
40
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presence of EtOH to give the highly reactive isothiocyanic acid
intermediate. Carboxylic acid hydrazides (1) immediately undergo
nucleophilic addition to become isothiocyanic acids, leading to
the corresponding stable thiosemicarbazides, of which acid-
catalyzed cyclodehydration occurs to form 2-amino-5-aryl-1,3,4-
thiadiazoles (2).
With the optimized reaction conditions in hand, we evaluated
the generality and scope of our methodology using a variety of
carboxylic acid hydrazides. The reactions of 1a–m with TMSNCS in
the presence of H2SO4 gave the 2-amino-1,3,4-thiadiazoles (2a–
m)32 in high yields (Table 2). Compound 2a (entry 1) was obtained
in the highest yield compared to those of the electron-rich and
electron-poor aryl-substituted derivatives 2b–i (entries 2–9). As we
observed, electron-withdrawing or electron-donating groups on
the phenyl ring of benzoic acid hydrazides successfully reacted. In
particular, 4-substituted derivatives 1b–e (entries 2–5) reacted
more efficiently than the corresponding 2-substituted regioi-
somers 1f–i (entries 6–9), possibly because of the steric hindrance
of the ortho substituent. To our delight, 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 aromatic and heteroaromatic acid hydrazides.
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Conclusions
In summary, we have devised a new, simple and efficient one-pot
protocol for the synthesis of 2-amino-1,3,4-thiadiazoles using
TMSNCS and carboxylic acid hydrazides as starting materials. This
experimental procedure is simple and does not require an
anhydrous solvent, inert gas atmosphere or chromatographic
purification. This method stands as a feasible alternative for
convenient access to 2-amino-1,3,4-thiadiazoles.
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RSC Adv., 2013, 3, 6813–6816 | 6815