Preparation of 1,4-Diamines by Enantio- and Diastereoselective Cu-Josiphos-Catalyzed Reductive Couplings of Azatrienes and Imines: Regiodivergence Enabled by Catalyst Structure and Reagent Tailoring.

We introduce a method for the 6,5-hydrofunctionalization of 2-azatrienes with N-phosphinoyl imine electrophiles under CuH catalysis to prepare 1,4-diamines bearing two stereogenic centers with excellent regio-, diastereo-, and enantiocontrol. In comparison to previously disclosed 6,3-hydrofunctionalizations of azatrienes with (Ph-BPE)CuH or (t-Bu-BDPP)CuH, the use of Josiphos SL-J001-1 as the supporting ligand facilitates regiodivergent introduction of the electrophile. We identify the electronic character of each phosphine of the ligand as critical to the observed regioselectivity and the utilization of an N-phosphinoyl group on the imine to be essential. Steric modification of the azatriene's activating group may enhance regioselectivity in challenging cases. Electronic modification of the N-phosphinoyl group can improve chemoselectivity to favor reductive coupling over imine reduction in several instances, a discovery that translates to couplings with other copper catalysts in forming 1,2-diamines. Experiments illustrate the delicate balance in favoring 1,4-diamine formation over all other processes and, along with density functional theory (DFT) calculations, lead us to a mechanistic proposal for this catalytic reaction.

Duke Scholars

Author Steven Malcolmson Chemistry