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

Abstract

The coupling reactions were performed using 3-ethoxy-4-iodo-5-methylisoxazole (4) as the key intermediate. Coupling of 4 under Suzuki–Miyaura or Stille conditions using Pd(PPh3)2Cl2 and arylboronic acids or aryltin analogues, 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. Under Heck reaction conditions using Pd(PPh3)2Cl2 and 4, analogues of 3-ethoxy-5-methylisoxazole containing vinylic or acetylenic groups in the 4-position were synthesized in yields ranging from 58 to 98%. 3-Ethoxy-5-methylisoxazol-4-ylmagnesium bromide (19), prepared from 4 and isopropylmagnesium bromide, reacted smoothly with benzaldehyde or benzoyl chloride to give the desired 4-[hydroxy(phenyl)methyl] analogue 21 and 4-benzoyl-3-ethoxy-5-methylisoxazole (22), respectively. Transmetallation of 19 with ZnCl2 and subsequent treatment with Pd(PPh3)2Cl2 and 4-iodotoluene gave 3-ethoxy-5-methyl-4-(4-methylphenyl)isoxazole (23) in 80% yield.