Andrea Castellin

Practical synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides via conventional and decarboxylative copper-free Sonogashira coupling reactions

Summary Two efficient protocols for the palladium-catalyzed synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides in the absence of copper were developed. A simple catalytic system consisting of Pd(OAc)2 and P(p-tol)3 using DBU as the base and THF as the solvent was found to be highly effective for the coupling reaction of 2-methyl-3-butyn-2-ol (4) with a wide range of aryl bromides in good to excellent yields. Analogously, the synthesis of aryl-2-methyl-3-butyn-2-ols was performed also through the decarboxylative coupling reaction of 4-hydroxy-4-methyl-2-pentynoic acid with aryl bromides, using a catalyst containing Pd(OAc)2 in combination with SPhos or XPhos in the presence of tetra-n-butylammonium fluoride (TBAF) as the base and THF as the solvent. Therefore, new efficient approaches to the synthesis of terminal acetylenes from widely available aryl bromides rather than expensive iodides and using 4 or propiolic acid rather than TMS-acetylene as inexpensive alkyne sources are described.

A convenient synthesis of the key intermediate of selective COX-2 inhibitor Etoricoxib

An original strategy for the synthesis of ketone 1, the key intermediate for preparing Etoricoxib, an important nonsteroidal anti-inflammatory drug, has been developed. Inexpensive 5-hydroxy-2-methylpyridine was converted to the corresponding acetyl derivative in four practical synthetic steps. The following palladium-catalyzed α-arylation of acetylpicoline with 4-bromo- or 4-chlorophenyl methyl sulfone was efficiently optimized in order to afford ketone 1 in remarkable yield.