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.
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.
Kercher
Timothy
T
Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, USA.
Rao
Chang
C
Bencsik
Josef R
JR
Josey
John A
JA
D000447:Aldehydes / Q000737:chemistry*; D000588:Amines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D004952:Esters / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D007093:Imidazoles / Q000138:chemical synthesis*; D008956:Models, Chemical; D009570:Nitriles / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry; D011137:Polystyrenes / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry