Diversification of the Three-Component Coupling of 2-Aminoheterocycles, Aldehydes, and Isonitriles: Efficient Parallel Synthesis of a Diverse and Druglike Library of Imidazo- and Tetrahydroimidazo[1,2-a] Heterocycles

Abstract

Due to their diverse range of biological activities, imidazoheterocycles are recognized as privileged structures making these structural motifs attractive targets for library preparation. We report herein the synthesis of a sizable collection of imidazo[1,2- a]heterocycle scaffolds well-suited for divergent library preparation by virtue of amine functional handles with diverse positioning and connectivities. Partial reduction of imidazo[1,2- a]pyrazines to the tetrahydroimidazo[1,2- a]pyrazines and regiospecific Mannich-type bond formation at the C-3 of imidazo[1,2- a]pyridine under mild conditions achieved additional topological and connective diversity within the scaffold collection. Subsequent parallel reaction of the functionalized imidazoheterocycles with polystyrene-tetrafluorophenol esters and sulfonates produced a 7500 compound library in high purity.

Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents

“…6 Distinct syntheses were designed and executed to obtain substitution at different positions of a piperazine ring. Scheme 2 summarizes how the 8-substituted piperazines were prepared.…”

Simple and Efficient: Ethylene Glycol Isonitrile Gold(I) Chlorides for the Formation and Stabilization of Gold Nanoparticles

“…3,6,9-Trioxadecylamine [35] (3b), 1-isocyano-2-methoxyethane [36] (5a), and [AuCl(SMe 2 )] [37] (6) were prepared according to literature procedures. All other chemicals were obtained commercially and used without further purification.…”

Recent advances in development of imidazo[1,2-a]pyrazines: synthesis, reactivity and their biological applications

“…A subsequent deprotection in acidic conditions resulted in moderate yields of 2,3-disubstituted imidazo[1,2-a]pyrazine 21 (Scheme 6). 36,37 3-Aminosubstituted imidazo[1,2-a]pyrazine 22 was synthesized by a microwave-assisted Ugi three-component coupling reaction between 2-aminopyrazine, benzylisonitrile and napthaldehyde, catalyzed by scandium triflate in methanol in 65% yield in a short reaction time. This methodology was found to be suitable for the rapid and efficient synthesis of fused heterocycles of pharmacological interest (Scheme 7).…”