An Arylation Strategy to Propargylamines: Catalytic Asymmetric Friedel-Crafts-type Arylation Reactions of C-Alkynyl Imines

The first arylation strategy for the synthesis of enantioenriched propargylamines is disclosed. This approach, which is complementary to previous alkynylation and alkylation strategies, involves a C(sp(2))-C(sp(3)) bond formation, and is based on the first asymmetric Friedel-Crafts-type arylation reaction of C-alkynyl imines. Asymmetric Friedel-Crafts reactions with electron-deficient phenols, a longstanding unsolved challenge, have thus been realized for the first time, enabled by the combination of our recently introduced C-alkynyl N-Boc-protected N,O-acetals as electrophiles and chiral phosphoric acids as catalysts. The synthetic utility of the resulting structurally diverse and polyfunctional chiral propargylamines was demonstrated by a series of selective transformations, including controlled reduction of the alkynyl group and iterative cross-couplings.