Palladium-catalyzed site-selective arylation of alkyl 2,4- and 2,5-dihalobenzoates with aryl titanium reagents

General methods for the highly site-selective monocoupling of alkyl 2,4- and 2,5-dihalobenzoates have been discovered. By switching from PdCl₂(PCy₃)₂/P(p-MeOPh)₃ to Pd(OAc)₂/L9, the preferred coupling site can be shifted from the C2-position to the C4 or C5-position. The formation of the substituted alkyl monohalobenzoate derivatives is highly site-selective and tolerant to both electron-withdrawing and electron-donating groups on aryl and heteroaryl titanium reagents and the reaction gives twenty-four substituted alkyl monohalobenzoate derivatives (except for 4ea, the other were novel compounds) were prepared and their structure was confirmed by FTIR, spectroscopy, ¹H and ¹³C NMR, and mass spectrometry. This simple synthetic route is designed to improve the rapid construction of mutiple aryl cross-coupling products.

Graphical abstract

The same substrate alkyl 2,4- and 2,5-dihalobenzoates can selectively generate C2-position and C4- or C5-position products by switching catalytic system from PdCl₂(PCy₃)₂/P(p-MeOPh)₃ to Pd(OAc)₂/L9. The reaction gives twentyfour substituted alkyl monohalobenzoate derivatives, and the simple synthetic route is designed to improve the rapid construction of mutiplearyl cross-coupling products.