Efﬁcient Domino Strategy for the Synthesis of Substituted
Xi Zhang, Kai Long, Jiayi He, Jialian Fu, Furen Zhang,
and Chunmei Li
School of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals
Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
E-mail: firstname.lastname@example.org; email@example.com
Received August 29, 2017
Published online 17 January 2018 in Wiley Online Library (wileyonlinelibrary.com).
An efﬁcient domino strategy for the synthesis of bipyrazole derivatives has been established successfully
as catalyst. This new reaction allows direct formation of highly functionalized bipyrazole de-
rivatives with a wide diversity in substituents in a one-pot manner. The present synthesis shows attractive
characteristics, such as the use of water as reaction media, simple one-pot operation, highly efﬁcient catalyst,
and mild reaction conditions.
J. Heterocyclic Chem., 55, 729 (2018).
In recent years, assembly of molecular diversity from
easily available starting materials with regard to
environmental and economic aspects constitutes a great
challenge in modern organic synthesis chemistry. Then,
the multicomponent domino reaction for the synthesis of
biologically and pharmacologically important active
molecules has become useful tools because of their
efﬁciency and green chemistry characteristic [1–4]. These
reactions avoid time-consuming and costly processes for
separation and puriﬁcation of precursors and tedious steps
of protection procedures [5–8]. Therefore, the
development of new domino reactions for diversity of
active molecules is a continuing challenge for modern
Heterocycles containing pyrazole rings belong to
important building blocks because of their diversity of
biological and pharmacological activities . These
compounds show anxiolytic , cholesterol formation-
inhibiting compounds , treatment of Alzheimer’s
disease, anorexia nervosa, drug and alcohol withdrawal
symptoms, drug addiction, and infertility activities .
In addition, they have also been reported as potent and
selective inhibitors of A1 adenosine receptor ,
inhibitors in immune and inﬂammatory cells , and
kinase inhibitors as anti-inﬂammatory drugs .
Because of the important biological activities of them,
these compounds have distinguished themselves as
heterocycles of profound chemical and biological
signiﬁcance [16–18]. Thus, the development of new
strategy for these compounds has attracted considerable
attention. A diversity of pyrazole and bipyrazole
derivatives has been synthesized using different starting
materials by various methods [19–23].
In recent years, our group has developed a series of
multicomponent domino reaction that can provide a lot of
multi-functionalized heterocyclic structures with chemical
and pharmaceutical interest . Recently, Puchala and
co-workers have reported a microwave-assisted reaction
between 1H-pyrazol-5-amines and aldehydes affording
structurally diverse pyrazole and dipyrazole derivatives
(Scheme 1, eq 1) . However, a new compound was
obtained when the 1H-pyrazol-5-amines, aldehydes, and
cyclohexanone were submitted to reaction system [24b].
As a continuation of our research, in this manuscript, we
would like to report a new chemistry approach for
bipyrazole derivatives that may be of potential chemical
and biomedical activities (Scheme 1, eq 2). This reaction
was carried out by mixing 1H-pyrazol-5-amines and
aldehydes in aqueous phase using Lewis acid Y(OTf)
catalyst at 80°C.
RESULTS AND DISCUSSION
An appropriate catalyst is of crucial importance in
successful organic transformations. First of all, we started
this methodology by mixing 3-methyl-1-phenyl-1H-
pyrazol-5-amine and benzaldehyde for goal product 3a as
model reaction with different catalysts (Scheme 2). The
results were summarized in Table 1. As shown in Table 1,
none of the product 3a was given without any catalysts.
Good yields (77–85%) of goal product 3a was obtained,
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