Palladium-Catalyzed Regioselective Arylation of Imidazo[1,2-b][1,2,4]triazine:  Synthesis of an α2/ 3-Selective GABA Agonist

• Published in: Journal of organic chemistry 2005-07, Vol.70 (15), p.5938-5945
• Main Authors: Gauthier, Donald R, Limanto, John, Devine, Paul N, Desmond, Richard A, Szumigala, Ronald H, Foster, Bruce S, Volante, R. P
• Format: Article
• Language: English
• Subjects: Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Organic chemistry; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0507035

A convergent, practical, and efficient synthesis of 2‘,6-difluoro-5‘-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABAA α2/ 3-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.