Asymmetric <i>para</i>-Selective aza-Friedel–Crafts Reaction of Phenols Catalyzed by Bulky PyBidine-Ni(OAc)₂

The conventional acid-catalyzed aza-Friedel–Crafts reaction of phenols with imines typically proceeds in an ortho-selective manner. A chiral bis(imidazolidine) pyridine (PyBidine)-Ni(OAc)2 catalyst switches the regioselectivity to para-selectivity. By replacement of the benzyl substituent of the parent PyBidine with a bulky Ph2CHCH2 substituent, the “bulky PyBidine”-Ni(OAc)2 catalyst enabled highly para-selective aza-Friedel–Crafts reactions (up to 99:1 para/ortho selectivity). With the assistance of a Sr(OAc)2 additive, a wide range of 3,5-dialkoxyphenols with sulfonylaldimines gave para-substituted products with up to 93% ee. DFT calculations suggest that the cooperative activation from nickel phenoxide formation (HOMO activation) and the hydrogen bonding activation of the sulfonylaldimine (LUMO activation) is the key for switching the regioselectivity.