A convenient synthesis of 4-substituted 3-ethoxy-5-methylisoxazoles by palladium-catalyzed coupling reactions

The coupling reactions were performed using 3-ethoxy-4-iodo-5-methylisoxazo le (4) as the key intermediate. Coupling of 4 under Suzuki-Miyaura or Still e conditions using Pd(PPh3)(2)Cl-2 and arylboronic acids or aryltin analogu es, respectively, gave 4-aryl substituted isoxazoles in yields ranging from 49% for the 3-pyridyl analogue 14, to 96% for the 4-pyridyl analogue 12. U nder Heck reaction conditions using Pd(PPh3)(2)Cl-2 and 4, analogues of 3-e thoxy-5-methylisoxazole containing vinylic or acetylenic groups in the 4-po sition were synthesized in yields ranging from 58 to 98%. 3-Ethoxy-5-methyl isoxazol-4-ylmagnesium bromide (19), prepared from 4 and isopropyl-magnesiu m bromide, reacted smoothly with benzaldehyde or benzoyl chloride to give t he desired 4-[hydroxy(phenyl)methyl] analogue 21 and 4-benzoyl-3-ethoxy-5-m ethylisoxazole (22), respectively. Transmetallation of 19 with ZnCl2 and su bsequent treatment with Pd(PPh3)(2)Cl-2 and 4-iodotoluene gave 3-ethoxy-5-m ethyl-4-(4-methylphenyl)isoxazole (23) in 80% yield. (C) 2001 Elsevier Scie nce Ltd. ALI rights reserved.