of 2-hydrazidopyrazine by addition of hydrazine to 2-chloro-
pyrazine involved the use of a large excess of hydrazine and
a tedious extractive workup. Furthermore, 2-chloropyrazine
is known to decompose under the reaction conditions. Thus,
a different synthetic approach was desired for scale-up.
An alternative synthetic method5 leading to benzo-fused
cases (route B, Scheme 1) involved the condensation of a
chloromethyloxadiazole with 1,2-phenylenediamine to afford
the desired benzene-fused [1,2,4]triazolo[4,3-R]piperazines
directly. The reaction conditions were rather harsh, and the
yields reported were low, which can be attributed to the poor
nucleophilicity of 1,2-phenylenediamine. The application of
this approach to the synthesis of 1a would result in milder
reaction conditions due to the enhanced nucleophilicity of
ethylenediamine and the electron-withdrawing nature of the
trifluoromethyl6 group.
Table 1. Use of Different Dehydrating Agents for the
Formation of Oxadiazolesa
The key intermediate chloromethyloxadiazole 3a was
prepared in two steps from commercially available materials
as shown in Scheme 2. Bishydrazide 2a was prepared in a
Scheme 2. Preparation of Oxadiazole 3a
a All reactions were run under reflux in acetonitrile.
The dehydration reaction can be run with a substoichio-
metric amount of phosphorus oxychloride using a catalytic
amount of DMAP. Comparable yields were obtained, albeit
in much longer reaction times. Lower yields or more
impurities were obtained when other dehydrating agents were
used.
Under the optimized conditions, 3a is obtained in 77-
80% yield after aqueous workup. While 3a can be isolated
by distillation, it was used directly in the next step following
removal of solvent.
When oxadiazole 3a was added to a solution of 2 equiv
of ethylenediamine in methanol at 0 °C, a new species
formed that was found to crystallize from the reaction
mixture at room temperature. This solid was isolated and
identified as the amidine 4a. Refluxing 4a in methanol for
4 h afforded the desired triazole 1a (Scheme 3).
one-pot procedure by reaction of 35% aqueous hydrazine7
with ethyl trifluoroacetate in acetonitrile and subsequent
addition of an acyl chloride and base. This procedure affords
the unsymmetrical bis(hydrazide) 2a, which can be isolated
by crystallization in higher than 95% yield.
Dehydration of 2a to obtain the desired oxadiazole 3a8
can be accomplished using a variety of known reagents. The
results for the preparation of oxadiazole 3a are summarized
in Table 1.
Although the best yield was obtained using phenylphos-
phonic dichloride (88%), the use of phosphorus oxychloride
was overall more desirable because of the comparable yield,
lower cost, and more benign waste streams.
Scheme 3. Preparation of Triazole 1a
(4) Nelson, P. J.; Potts, K. T. J. Org. Chem. 1962, 27, 3243-3248.
(5) Makino, T.; Kato, T. JP06128261(A), 1994.
(6) Perfluoroalkyl-substituted oxadiazoles are known to react readily with
ammonia at room temperature to produce triazoles. (a) Brown, H. C.; Cheng,
M. T. J. Org. Chem. 1962, 27, 3240-3243. (b) Brown, H. C.; Cheng, M.
T.; Parcell, L. J. J. Org. Chem. 1961, 26, 4407-4409. (c) Reitz, D. B.;
Finkes, M. J. J. Heterocycl. Chem. 1989, 26, 225-230. (d) Reitz, D. B.;
Finkes, M. J. J. Org. Chem. 1989, 54, 1760-1762. (e) Barlow, M. C.; Bell,
D.; O’Reilly, N. J.; Tipping, A. E. J. Fluorine Chem. 1983, 23, 293-299.
(7) A nonexplosive form of hydrazine is used as the limiting reagent.
Hydrazine is completely consumed after the addition of trifluoroacetate. In
this manner, no hazardous waste containing hydrazine is generated.
(8) (a) Perez, M. A.; Bermejo, J. M. J. Org. Chem. 1993, 58, 2628-
2630. (b) Tashtoush, H.; Al-Talib, M.; Odeh, N. Ann. Chem. 1992, 1992,
291. (c) Al-Talib, M.; Tashtoush, H.; Odeh, N. Synth. Commun. 1990, 20,
1811-1817. (d) Shi, W.; Qian, X.; Song, G.; Zhang, R.; Li, R. J. Fluorine
Chem. 2000, 106, 173-179. (e) Mogilaiah, K.; Chowdary, D. S.; Rao, R.
B. Indian J. Chem. Sect. B 2001, 40, 43-48.
Further investigation of this reaction revealed that the
amidine formed readily at -40 °C. At temperatures higher
than 5 °C, the intermediate amidine 4a slowly cyclizes to
1040
Org. Lett., Vol. 7, No. 6, 2005