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Chapter 1
Synthesis of functionalized pyrimidines
Figure-16
Solid phase synthesis
The generation of combinatorial libraries of heterocyclic compounds by solid
phase synthesis is of great interest for accelerating lead discovery and lead
optimization in pharmaceutical research. Multi-component reactions (MCRs) 35,36-37
leading to heterocycles are particularly useful for the creation of diverse chemical
libraries, since the combination of any 3 small molecular weight building blocks in a
single operation leads to high combinatorial efficiency. Therefore, solid phase
modifications of MCRs are rapidly become the cornerstone of combinatorial synthesis
of small-molecule libraries.
The first solid-phase modification of the Biginelli condensation was reported
by Wipf and Cunningham 38 in 1995 (Figure-17). In this sequence, γ-aminobutyric
acid derived urea was attached to Wang resin using standard procedures. The
resulting polymer-bound urea was condensed with excess β-ketoester and aromatic
aldehydes in THF at 55 °C in the presence of a catalytic amount of HCl to afford the
corresponding immobilized DHPMs. Subsequent cleavage of product from the resin
by 50 % trifluoroacetic acid (TFA) provided DHPMs in high yields and excellent
purity.
Figure-17
Li W. and Lam Y. 39 have described the synthesis of 3,4-dihydropyrimidin-2-
(1H)ones/thiones using sodium benzene sulfinate as a traceless linker (Figure-18).
The key steps involved in the solid-phase synthetic procedure were sulfinate
acidification, condensation of urea or thiourea with aldehydes and sulfinic acid and
traceless product release by a one-pot cyclization-dehydration process. Since a variety
of reagents can be used, the overall strategy appears for library generation.
Department of Chemistry, Saurashtra University, Rajkot-360005 9