Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-selective GABA agonist

• Published in: Journal of organic chemistry Vol. 70; no. 15; pp. 5938 - 5945
• Main Authors: Gauthier, Jr, Donald R, Limanto, John, Devine, Paul N, Desmond, Richard A, Szumigala, Jr, Ronald H, Foster, Bruce S, Volante, R P
• Format: Journal Article
• Language: English
• Published: United States 22.07.2005
• Subjects: Acetaldehyde - analogs & derivatives; Acetaldehyde - chemistry; Bromides - chemistry; Catalysis; GABA Agonists - chemical synthesis; Hydrocarbons, Aromatic - chemistry; Imidazoles - chemistry; Palladium - chemistry; Receptors, GABA-A; Stereoisomerism; Structure-Activity Relationship; Triazines - chemical synthesis; Triazoles - chemistry
• 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 GABA(A) alpha(2/3)-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.