3432
K.-S. Yeung et al. / Tetrahedron Letters 46 (2005) 3429–3432
it only applied to acetamidine and benzamidine: Francis,
J. E.; Gorczyca, L. A.; Mazzenga, G. C.; Meckler, H.
Tetrahedron Lett. 1987, 28, 5133.
under these conditions. Finally, the aliphatic nitrile 19a
(entry 12) also participated as a substrate, providing tri-
azole 19c, albeit in modest yield. This appears to be a
limitation of this process since the simpler aliphatic
derivatives, acetic, and formic hydrazide, reacted with
benzonitrile to provided triazole products in yields of
only 14% and 12%, respectively. However, the thiophenyl-
substituted acetic hydrazide derivative 14b participated
as a reaction partner to provide products 14c and 18c
in moderate yields (entries 7 and 11).
5. (a) In our laboratories, Shimadzu analytical LC/MS and
preparative HPLC with auto-sampling are used; (b) The
automation capacity of a microwave synthesizer that can
be coupled to the Shimadzu instruments is also an
attractive feature for this purpose.
6. (a) Neat thermal fusion between benzonitrile (5) and
hydrazides at 230 °C: Weidinger, H.; Kranz, J. DE Patent
1076136, 1958; (b) Reaction between benzonitrile (5) and
benzoic hydrazide (6) in refluxing MeOH provided a
mixture of 1,2,4-triazole (26%) and 1,3,4-oxadiazole
(20%): Neelima; Bhaduri, A. P. Indian J. Chem. 1993,
22B, 79.
In summary, an expedient synthesis of 3,5-disubstituted
1,2,4-triazoles that proceeds by the direct reaction of a
nitrile and a hydrazide in the presence of catalytic
7. For recent reviews see: (a) Kappe, C. O. Angew. Chem.,
Int. Ed. 2004, 43, 6250; (b) Hayes, B. L. Aldrichim. Acta
2004, 37, 66.
n
amount of K2CO3 in BnOH has been developed. The
scope of this process has been demonstrated by examin-
ing reaction partners that incorporate a range of elec-
tron-donating and withdrawing functional groups and
heterocycles, all of which are readily tolerated. The reac-
tion of nitriles anticipated to be relatively unreactive
also proceeded to provide the desired products. Thus,
diverse, small molecule, drug-like structures can be
assembled in a solution phase, automated synthesis
fashion enabling expeditious SAR studies.
8. (a) The insignificant difference in yield between microwave
and oil bath conditions when using 0.5 equiv of K2CO3
was presumably because the equilibration of temperature
was equally achieved over the 3 h under both conditions,
and assuming equal internal pressure. Perreux, L.; Loupy,
A. Tetrahedron 2001, 57, 9199; (b) Lidstro¨m, P.; Tierney,
J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
9. All reagents were used as received from commercial
sources. A representative procedure is as follows: A
mixture of nitrile (3 mmol), hydrazide (1 mmol), and
K2CO3 (0.5 mmol) in nBuOH (2mL) in a microwave
synthesizer tube was placed under microwave irradiation
in an Emrys Optimizer (Personal Chemistry) with normal
absorption level and the temperature set to 150 °C.
Alternatively, the mixture was stirred in a reusable sealed
tube at 150 °C in an oil bath. The progress of the reaction
was monitored by the disappearance of the hydrazide
using LC/MS. After completion, the mixture was evapo-
rated, diluted with MeOH, and then purified by reverse
phase preparative HPLC (MeOH/H2O/0.1% TFA). Due
to concern about the stability of the hydrazides over the
>1 h time period under the basic reaction conditions,
3 equiv of the nitriles were used in all examples. In general,
hydrazides show toxicity (e.g., hepatotoxicity), which is
usually because of the formation of reactive radical
metabolites in vivo.
Acknowledgements
We thank Katharine Grant-Young for proof-reading
the manuscript.
References and notes
1. Alanine, A.; Anselm, L.; Steward, L.; Thomi, S.; Vifian,
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10. This protocol was found to be incompatible with the
presence of nitroaromatic derivatives in either reaction
partner. Complex reaction mixtures containing insignifi-
cant amounts of product were obtained when either
nitrobenzonitrile or nitrobenzoic hydrazide were used.
11. Duggen, D. E.; Noll, R. M.; Baer, J. E.; Novello, F. C.;
Baldwin, J. J. J. Med. Chem. 1975, 18, 900.
4. A high yielding synthesis of 3,5-disubstituted 1,2,4-triazole
from the less reactive amidine has been reported, however,