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ADVANCES
IN TRIAZOLE
CHEMISTRY
ADVANCES
IN TRIAZOLE
CHEMISTRY
TAHIR FAROOQ
Assistant Professor,
Department of Applied Chemistry,
Government College University,
Faisalabad, Pakistan
Elsevier
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This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein. In
using such information or methods they should be mindful of their own safety and the safety of
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To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.
I dedicate this piece of work to my lovely kids (Zoraiz and Areshva) and late father
who didn’t live long enough to see me prosper.
Preface
xiii
xiv Preface
increasingly efficient, versatile, and mild and furthermore allow for regi-
oselective introduction of substituents has been fueled by the ubiquity of
these heterocycles in compounds of interest in the pharmaceutical and ag-
rochemical sectors. Medicinal interest in 1,2,4-triazoles has centered on
their antibacterial and antifungal properties with the discovery by Pfizer of
the antifungal blockbuster fluconazole in 1981 being a notable milestone.
The agrochemical sector’s fascination with these “symmetric” triazoles as
herbicides and fungicides was also intense in the 1970s and 80s following
Bayer’s discovery of the cereal protective triazole fungicide triadimefon.
In Advances in Triazole Chemistry,Tahir Farooq guides the reader expertly
through a myriad of methods for the synthesis of triazoles. He explores the
use of 1,2,3- and 1,2,4-triazoles as bioisosteres in medicinal chemistry and
as novel bases in (oligo)nucleotide chemistry. He also reviews the use of
triazoles as components of smart polymers, glycoconjugates, and function-
alized nanomaterials as well as highlighting the role of the triazole motif
in plant growth regulators, in peptidomimetics, in coordination complexes,
and in myriad areas of materials science. It is a feast of chemistry that beau-
tifully illustrates the incredible versatility and power of synthesis to create
new structures with designed properties of utility across a broad swath of
science.
The humble triazole has come a long way in the last 60 years, and this
book provides a great overview of this journey and the plethora of applica-
tions for which this five-membered aromatic heterocycle has proven to be
a critical structural component. It should prove of value to chemists both
wanting to familiarize themselves with this fascinating area of chemistry
and wanting to appraise themselves of latest developments.
Tahir Farooq
Department of Applied Chemistry, Government College University, Faisalabad, Pakistan
Amjad Hameed
Nuclear Institute for Agriculture and Biology (NIAB), Faisalabad, Pakistan
Arruje Hameed
Department of Biochemistry, Government College University, Faisalabad, Pakistan
Ali Raza
Department of Applied Chemistry, Government College University, Faisalabad, Pakistan
xi
CHAPTER 1
Introduction
In recent times, heterocyclic chemistry has been recognized as a most chal-
lenging field, but it is still a significantly rewarding forefront because of
heterocycles as the major class in organic chemistry.1 Predominantly, het-
erocycles are found in biologically active pharmaceuticals, agrochemicals,
and most additives and modifiers commonly employed in various industrial
applications. Owing to their incredible capacity to accommodate a diverse
range of substituents around a core structure, in addition to their charac-
teristic structural features, they have always been under keen consideration
of medicinal chemists for the construction of new bioactive compounds.
In connection to this, the design and development of nitrogen-rich het-
erocycles has attracted much interest over the recent past years. Triazoles
are the most promising heterocycles exhibiting a broad spectrum of chem-
ical, agrochemical, and biological properties.2 Ever-increasing worth of this
privileged motif has quickened the development of many facile synthetic
strategies during the last few years.
Triazole is a five-membered heterocycle containing three nitrogen at-
oms at 1, 2, and 3 or 1, 2, and 4 positions. Triazole exists in the following
forms (Figure 1):
1,2,3-Triazoles
Over the past few years, 1,2,3-triazoles have received much attention by
the scientific community as exhibited by its scope of applications in various
disciplines including material science, organometallic, combinatorial, and
synthetic medicinal chemistry as well as in agrochemicals.2–4 Furthermore,
1,2,3-triazolic compounds are extensively used as dyes and related materials,
corrosion inhibitors, optical brightening agents, and also as p hotostabilizers.5
Indeed, their notable stability across a range of severe conditions has acti-
vated their usefulness in pure and applied chemical sciences.6
Some of the structural features advantageously required in the context
of developing drug delivery systems and for nanomedicine have also been
represented by triazole moiety. For example, as a consequence of high ar-
omatic stabilization, they can withstand acid or basic hydrolysis, oxidizing
and or reducing conditions. Similarly, this splendid moiety survives over
a wide scale of pH in various solvents. This has also been exhibited by its
remarkable resistance to various metabolic degradation processes in living
systems (Figure 2).7,8
In fact, the 1,4-disubstituted 1,2,3-triazoles are not a newly intro-
duced category for medicinal chemists. Before the recent notable develop-
ments in strategies for triazole synthesis, more than 7000 1,4-disubstituted
1,2,3-triazolic compounds were known with excellent bioactivities.9 They
were known to display a broad spectrum of activities including selective β3
adrenergic receptor inhibition,10 antibacterial,11 anti-histamine activity,12
anti-HIV,13 and potent anti-viral14 properties. Desired improvements in
the pharmacokinetic profiles of antibiotics were achieved by incorporating
a triazole motif. The β-lactamase inhibitory potential of tazobactam was
found to be dependent on the presence of triazole ring.15
In Figure 3 are some of the triazolic drugs that are well-known com-
pounds with their bioactive potential before the advent of modern click
chemistry.9,17,18
Synthesis of 1,2,3-triazoles
The broad utility of 1,2,3-triaoles across a range of scientific disciplines
for the construction of novel molecular architectures has resulted in
procedural modifications and development of new synthetic methods
1,4,5-Trisubstituted 1,2,3-triazoles
Ru-catalyzed synthesis of 1,4,5-trisubstituted 1,2,3-triazoles
In addition to earlier well-explained, regioselective, Ru-catalyzed methodol-
ogy for the synthesis of 1,5-disubstituted 1,2,3-triazoles, Sarpless group also
reported the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles. Initially, they
presented the following single case with symmetrical alkyne (Scheme 9).
In 2006, Weinreb35 and his team further explored the scope and gener-
ality of the ruthenium-catalyzed cycloadditions of unsymmetrical alkynes
and alkyl azides (Scheme 10).
As indicated by this outcome, it was observed that during the synthesis
of 1,4,5-trisubstituted 1,2,3-triazoles, the substitution patterns of electron-
ically or sterically biased unsymmetrical alkynes principally control the re-
gioselectivity of the product. However, no rational explanation was given
explaining the regioisomeric ratios.