Asymmetric para-Selective aza-Friedel-Crafts Reaction of Phenols Catalyzed by Bulky PyBidine-Ni(OAc)2

The conventional acid-catalyzed aza-Friedel-Craftsreactionof 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 parentPyBidine with a bulky Ph2CHCH2 substituent,the bulky PyBidine-Ni(OAc)(2) catalyst enabledhighly para-selective aza-Friedel-Crafts reactions(up to 99:1 para/ortho selectivity).With the assistance of a Sr(OAc)(2) additive, a wide rangeof 3,5-dialkoxyphenols with sulfonylaldimines gave para-substituted products with up to 93% ee. DFT calculations suggestthat the cooperative activation from nickel phenoxide formation (HOMOactivation) and the hydrogen bonding activation of the sulfonylaldimine(LUMO activation) is the key for switching the regioselectivity.

Automated summary

The conventional acid-catalyzed aza-Friedel-Crafts reaction of phenols with imines typically shows ortho-selectivity. However, a chiral bis(imidazolidine) pyridine (PyBidine)-Ni(OAc)(2) catalyst can switch the regioselectivity to para-selectivity. This switch is facilitated by the bulky PyBidine-Ni(OAc)(2) catalyst with a Ph2CHCH2 substituent, resulting in highly para-selective aza-Friedel-Crafts reactions (up to 99:1 para/ortho selectivity).