Pd-Catalyzed Monoselective <i>ortho</i>-C–H Alkylation of <i>N</i>‑Quinolyl Benzamides: Evidence for Stereoretentive Coupling of Secondary Alkyl Iodides

We report a method for the monoselective alkylation of ortho-C–H bonds of N-quinolyl benzamides with both primary and secondary alkyl halides under palladium catalysis. With promotion by NaHCO3 and (BnO)2PO2H or (PhO)2PO2H, symmetric benzamide substrates can be selectively ortho-alkylated to give either mono- or dialkylated products by simply adjusting the amount of NaHCO3 applied. The use of phosphate notably improves the alkylation yield, although it may not be directly involved in C–H palladation or the subsequent functionalization step. Kinetic isotope effect studies indicate that C–H palladation is not the rate-limiting step. Examination of the reactions of an isolated palladacycle intermediate with both cis- and trans-4-methylcyclohexyl iodides revealed surprising stereoretentive couplings of these alkyl iodides. This evidence strongly suggests that the functionalization of the palladacycle with secondary alkyl iodides proceeds via a rarely precedented concerted oxidative addition pathway.