CL-130908
Received: October 2, 2013 | Accepted: October 12, 2013 | Web Released: October 19, 2013
Facile One-pot Synthesis of Some Novel Thiazolylpyrazole Derivatives with Antifungal Activity
Ya-Li Song, Tao Yang, Yun-Fang Dong, Fan Wu, and Geng-Liang Yang*
Key Laboratory for Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Science,
Hebei University, Wusi East Road No. 180, Baoding 071002, P. R. China
(E-mail: ygl@hbu.edu.cn)
A series of novel 1-(4-phenylthiazol-2-yl)-1,4-dihydrothio-
chroman[4,3-c]pyrazole have been prepared by a three-compo-
nent reaction of thiochromanone-3-carbaldehyde, phenacyl
bromide, and thiosemicarbazide. The reaction was in one-pot
and did not require any additional catalyst with moderate yields.
This method provided several advantages such as environment
friendliness and simple work-up procedure. The compounds
were assayed for antifungal activity and some of the new
compounds can be further utilized as lead compounds.
ketones with thiosemicarbazide generating thiosemicarbazone,
which on reaction with phenacyl bromide gives the products.12
Some literature describes the one-pot synthesis of thiazolylpyr-
azole derivatives recently, but all of them need additional
catalyst.13 Herein, we efficiently synthesized some thiazolylpyr-
azole derivatives containing thiochroman skeleton by a one-pot
three-component reaction without additional catalyst, some of
which shows antifungal activity.
Reaction of an equimolar mixture of thiochromanone-3-
carbaldehyde,14 phenacyl bromide, and thiosemicarbazide under
reflux in EtOH gave the final products (Scheme 1). In this
reaction, the assembly of thiazolylpyrazole derivatives 4
comprises the following key steps (Scheme 2): intermediate I,
the adduct of thiochromanone-3-carbaldehyde 1 to thiosemicar-
bazide 2, reacts with phenacyl bromide 3 to give the inter-
mediate II undergoing the final ring closure. Likely the HBr
eliminated from the Hantzsch thiazole synthesis (I ¼ II) plays a
role of catalyst in the cyclocondensation of pyrazole.
This rationale has been proven by the synthesis of
intermediate I from 6-chloro-4-methoxythiochromane-3-carbal-
dehyde and thiosemicarbazide in EtOH without any catalyst.
That means thiochromanone-3-carbaldehyde and thiosemicarba-
zide cannot cyclize to pyrazole without catalyst. Intermediate I
readily cyclizes to the corresponding thiazolylpyrazole deriva-
tive after adding phenacyl bromide thus confirming the cyclo-
condensation of pyrazole is catalyzed by in situ generated HBr
as the above rationale suggests.
All of the synthesized compounds in Table 1 gave analytical
and spectroscopic data which were consistent with their depicted
structures (The analytical data of all the synthesized compounds
are given in Supporting Information.)15
Fungal infections are a growing problem because of
extensive use of antibiotic drugs and medical instruments.1
However, clinically used antifungal drugs widely exhibit low
bioavailability, narrow antimicrobial spectrum, toxic side
effects, and other problems.2 Therefore, new effective antifungal
drugs are desired all the time.
Thiochromanone is a versatile reagent that has been
extensively utilized in heterocyclic synthesis.3 It had been
reported to possess important biological activities such as
antifungal4 and anticancer5 activities. Thiazole and pyrazole
are also the key scaffolds of many biological molecules and
pharmaceutical products because of their ubiquitous nature.
Many of their derivatives had been reported with fantastic
bioactivities. A large number of thiazole derivatives obtained
from microbial and marine origins exhibit important biological
effects such as antibacterial,6 antifungal,7 antitumor,8 and anti-
hypertensive9 activities. Pyrazole derivatives have been also
reported to exhibit significant antimicrobial10 and antifungal11
activities.
In view of the various biological activities of thiazole and
pyrazole, we were tempted to synthesize a series of compounds
constructed of thiochromanone combined with thiazolylpyrazole
as potential antifungal agents. To the best of our knowledge,
these thiazolylpyrazole derivatives containing thiochromanone
have not been reported to date.
The 1H NMR spectrum of 4o showed a sharp singlet at
3.84 ppm due to the C-4 proton of the compound. The singlet
at 3.84 ppm is related to a singlet at 7.65 ppm in an NOE
experiment, which means the sharp singlet at 7.65 ppm is the
proton of pyrazole. Thiazole proton is another singlet at
7.23 ppm. Aromatic proton peaks of two phenyl rings of 4o
appear in the region of 8.69-6.97 ppm as multiplets. The
Commonly, thiazolylpyrazole derivatives are formed via
base-catalyzed or acid-catalyzed reaction of α,β-unsaturated
Scheme 1. Synthesis route of thiazolylpyrazole derivatives 4a-4s.
© 2014 The Chemical Society of Japan
Song, Ya-Li
