Pd-catalyzed monoselective ortho-C-H alkylation of N-quinolyl benzamides: evidence for stereoretentive coupling of secondary alkyl iodides

J Am Chem Soc. 2015 Jan 14;137(1):531-9. doi: 10.1021/ja511557h. Epub 2014 Dec 19.


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.