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Download fileKey Intermediates in Combinatorial Chemistry: Access to Various Heterocycles from α,β-Unsaturated Ketones on the Solid Phase
journal contribution
posted on 1998-01-22, 00:00 authored by Andreas L. Marzinzik, Eduard R. FelderThe value of α,β-unsaturated ketones as key intermediates for
the combinatorial assembly of four
different templates on the solid phase, namely pyrimidines,
dihydropyrimidinones, pyridines, and
pyrazoles, was explored with individual syntheses of variably
substituted model compounds.
Starting from aldehydes grafted on polystyrene support, the Wittig
and the Claisen−Schmidt
reaction conditions were adapted to efficiently prepare
α,β-unsaturated ketones on the solid phase.
Further derivatization of the α,β-unsaturated ketones to form
pyrimidines succeeded with a number
of amidines. In a feasibility study, the potential to obtain, in a
modular fashion, other small
heterocycles from the same intermediates was assessed. In this
solid-phase approach α,β-unsaturated carbonyl intermediates can act as a three-carbon component
and a primary enamine
is utilized to complement the system for pyridine ring formation.
Instead, with N-methylurea a
dihydropyrimidinone is obtained. As an alternative, substituted
hydrazines are incorporated in
one orientation, providing pyrazoles with defined regioisomerism.
The study indicates that α,β-unsaturated ketones grafted on the solid phase can take a pivotal role
as branching points in a
number of synthetic diversity schemes and, therefore, represent
versatile intermediates for the
efficient preparation of combinatorial small molecule
libraries.