Authors: Bryce Tolman, Jasper Terungwa Iorkula , Justin Singleton, Matt Peterson
Mentors: Matt Peterson
Insitution: Brigham Young University
An efficient method for preparing C-3 aminated pyrazolo[1,5-a]pyrimidines was developed. The method consisted of treating 3-bromopyrazolo[1,5-a]pyrimidine with a wide range of 1° or 2° alkylamines with CuI (20 mol%), L-proline (40 mol%), and Et 3 N (2 equiv) in DMSO under microwave heating conditions (130 °C, 4 hours). C-3 aminated products were obtained in good to excellent isolated yields (54–90%; ave. yield = 77%), and represents the most broadly applicable, non-palladium-catalyzed amination of 3-bromopyrazolo[1,5-a]pyrimidine ever reported. The coupling worked well for unfunctionalized 1° alkylamines such as butylamine, benzylamine, isopropylamine or cyclohexylamine, and more densely functionalized 1° amines with CH 2 - or CH 2 CH 2 -linked heterocycles were also well tolerated (e.g. pyridine-, indole-, thiophene-, and furan-linked methyl- or ethylamine derivatives). 2° Alkylamines such as morpholine, pyrrolidine, and piperidine also reacted well under these conditions. Heating under conventional oil-bath conditions required a more extended reaction time (40 h), but also gave products in good yield (72-76%) for both 100-mg and gram-scale reactions. A pegylated azide (11-azido-3,6,9-trioxaundecan-1-amine) was also coupled in good yield (65% yield microwave), demonstrating compatibility of this methodology for potential click-type applications. Our method is simple and efficient, and avoids drawbacks associated with alternative methods, including long reaction times, limited substrate scope, and required use of air-sensitive/extremely expensive palladium catalysts and specialized synthetic ligands.