Abstract |
Multicomponent reactions (MCRs) are highly efficient one-pot synthetic
approaches for the synthesis of complex and versatile scaffolds. To date, these
reactions are considered pillars of medicinal and organic chemistry.
Surprisingly, their application in drug discovery and material science is still
limited, considering their merits. For example, to the best of our knowledge,
MCRs are barely used in material chemistry, particularly towards the synthesis
of organic electronic materials such as tetrathiafulvalene (TTF)-based
derivatives.
In this thesis, exploitation of the MCRs applications in both drug design and
material science occurred. Compared with the traditional synthetic protocols, the
proposed novel MCR procedures are of higher quality due to the following
characteristics: mild conditions, speed, commercially available starting
materials, easily scale up approaches and reduced purification steps. In this
study, several bioactive and organic electronic materials via MCRs are
developed. Herein, five chapters are dealing with the utilization of the MCRs. In
summary, more than 160 molecules are obtained and most of these potential
adducts are first time synthesized.
Chapter 1 deals with numerous functionalized indole tetrazole derivatives
resulting via a green, easy and rapid two-step Ugi-tetrazole four component (UT4CR) procedure from commercially available anilines, aldehydes and TMSN3 in
good to excellent yields. Catalytic hydrogenation and additional MCRs are
employed to demonstrate the potential of this synthetic protocol. Additionally,
this method is gram-scalable and one-pot feasible. Interestingly, an eIF4A3
inhibitor is obtained via this de novo protocol.
Chapter 2 exploits the classical Ugi four component reaction (U-4CR) to C2
functionalized indole amides. Excitingly, 20 derivatives are isolated from anilines,
glyoxal dimethyl acetal, formic acid and isocyanides via an innovative 2-step
protocol in good to excellent yields. These novel indole syntheses have several
advantages, such as speed, highly sustainable, mild reaction conditions, low
toxicity of the building blocks, high safety standards, broad substrate scope and
good yields. This gram-scalable synthetic method is an easier and faster
alternative in order to access numerous bioactive molecules. We have exploited
all the above by the preparation of 2t, an anti-tuberculosis agent; it has
demonstrated excellent features, such as time, amounts of inorganic and
organic solvents, process mass intensity (PMI), E-factor and atom economy
(AE). Additionally, the SETD2 inhibitor (2r) and another anti-tuberculosis agent
(2s) are also obtained simply under our protocol.
Chapter 3 presents a library of 45 dibenzothiazepines and benzothiazepines
via five different MCRs. Those scaffolds are widely used in biology and material
science. Interestingly, most of these polycyclic and rigid dibenzothiapines with
high complexity obey to the rule of 5 (Ro5) according to the CSD analysis. In
addition, several single crystal structures of these compounds have been solved,
offering insights for their potential binding mode.
The fluorene structural motif is widely present in numerous natural products
and bioactive compounds. This scaffold is a useful candidate in materials
science and drug discovery. In Chapter 4, a library of 23 fluorene-fused
derivatives is depicted through IMCRs. These novel scaffolds are synthesized
by functionalizing a fluorene building block. This work shows the huge potential
of the MCRs in the diversity and complexity of fluorene-based compounds.
Chapter 5 expands the scope of the MCRs on the functionalization of TTF to
obtain numerous electronic adducts. Herein, more than 30 TTF-fused
compounds obtained via four different MCRs. In addition, the synthesis of
molecules with a D-A or D-π-A system occurred (Scheme 4). This important
feature allows an intramolecular charge transfer (ICT) to occur. The single X-ray
structure displays a planar character that could help the electron delocalization.
What’s more, electronic measurements such as Hall measurement, the energy
gap between the HOMO and LUMO, and the measurement of resistance are
employed. So far, the applications of the TTF-based derivatives with D-A
systems in organic semiconductors and molecular machines fields are limited
by the efficient methods. Arguably, the new procedures will build a library of
various TTF derivatives and facilitate the rapid development of novel materials.
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