desired product 4aah in 73% yield (Table 2, entry 8). Unfortu-
nately, the internal alkyne 3i, when allowed to react with benz-
aldehyde 1a and phenylhydrazine 2a failed to give the desired
product (Table 2, entry 17).
Resources (Guangxi Normal University), Ministry of Education
of China (CMEMR2011-15), and Guangxi Natural Science
Foundation
of
China
(2012GXNSFAA053027,
2011GXNSFD018010 and 2010GXNSFF013001) for financial
Beside the above alkynes, a variety of aldehydes 1a–1f and
hydrazine 2a–2c were studied and underwent smooth transform-
ation affording the desired products in good yields (Table 2,
entries 9–16). Among the examined aldehydes 1a–1f, aldehydes
1b (R1 = 4-MeOC6H4) and 1c (R1 = 4-MeC6H4) gave the
desired products in higher yields (Table 2, entries 9 and 10). For
the reactions with other aldehydes, such as 4-chlorobenzalde-
hyde and 4-nitrobenzaldehyde, the corresponding pyrazoles 4
were obtained in a bit lower yields (Table 2, entries 11, 13 and
14). Additionally, aldehydes bearing a heterocyclic aromatic sub-
stituent such as 2-thiophenaldehyde (R1 = 2-thienyl) treated with
phenylhydrazine 2a and phenylacetylene 3a in the presence of
10 mol% PTSA giving the desired product 4eaa in 71% yield
(Table 2, entry 12). Moreover, substrate 2b possessing an elec-
tron-donating group (R2 = 4-MeOC6H4) on the benzene ring
gave the desired product 4abd in 78% yield; whereas, 2c posses-
sing an electron-withdrawing group (R2 = 4-NO2C6H4) on the
benzene ring gave the desired product 4aca in 63% yield
(Table 2, entries 15 and 16). It should be noted that functional
groups such as fluoro, chloro, bromo, nitro, and methoxy, are tol-
erated under the reaction conditions. The reaction proceeded
smoothly under mild conditions and air was tolerated.
In summary, we have developed an effective Mannich-type–
cyclization–oxidation tandem reaction for the synthesis of 1,3,5-
substituted pyrazoles directly from readily available aldehydes,
hydrazines and alkynes, using PTSA as a multifunctional cata-
lyst. A wide range of alkynes, bearing not only aryl groups but
also alkyl groups, effectively participated in the reactions. Also,
a number of functionalities, such as fluoro, chloro, bromo, nitro,
and methoxy, are tolerated under the reaction conditions. This
reaction system can be carried out under mild conditions which
give a rapid access to a variety of pyrazoles.
support.
Notes and references
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4 During the preparation of this manuscript, Suzuki and co-workers reported
a gold-catalyzed three-component annulation of alkynes, hydrazines, and
aldehydes/ketones for the synthesis of polysubstituted dihydropyrazoles.
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5 There have been reports of some Mannich-type coupling reactions of term-
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Acknowledgements
We thank the project 973 (2011CB512005), Key Laboratory for
the Chemistry and Molecular Engineering of Medicinal
4698 | Org. Biomol. Chem., 2012, 10, 4696–4698
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