SYNTHESIS OF 2,5-DISUBSTITUTED FURANS VIA PALLADIUM-CATALYZED ANNULATION OF ALKYL 3-OXO-6-HEPTYNOATES

The reaction of the readily available alkyl 3-oxo-6-heptynoates with a ryl halides in the presence of K2CO3 and catalytic amounts of Pd(PPh3) (4) at 100 degrees C provides a valuable new route to 2,5-disubstitute d furans 3. Most probably, the furan ring is generated through an annu lation reaction promoted by sigma-arylpalladium complexes generated in situ and involving the nucleophilic attack of the ketonic oxygen acro ss the carbon-carbon triple bond coordinated to palladium, followed by the base-catalyzed isomerization of the resultant stereoisomeric 2,5- dialkylidenetetrahydrofuran intermediates 4 and 5. The reaction is hig hly chemoselective. No evidence was obtained of carboannulation produc ts. The reaction temperature has proven to be crucial for the success of the methodology. The K2CO3:alkyne ratio also affects the reaction o utcome. The highest yields of furan derivatives have been obtained wit h aryl halides containing electron-withdrawing substituents, very like ly because the higher acidity of the methylene protons of 4 and 5 favo rs the isomerization step. Extension of the methodology to methyl 3-ox o-7-substituted-6-heptynoates leads to the formation of 2,5-disubstitu ted furans containing a branched side chain. The presence of an alkyl substituent on the C-2 of the staring alkyne, however, seems to preven t the isomerization step. Treatment of ethyl 2-methyl-3-oxo-6-heptynoa te under our standard conditions produced in fact the 2,5-dialkylidene derivative 5p in 42% yield, and no evidence of the corresponding fura n derivative was attained.