Rh-Catalyzed Chemo-and Enantioselective Hydrogenation Of Propargyl Imine

Chiral propargylamines are important intermediates for synthesis of polyfunctional amine derivatives and bioactive compounds.They are used to synthesize the antibiotic substance(+)-Streptazolin and D-desosamine which is the building block of several vital macrolide.Additionally,optically pure propargylic amines are found in the medicinally relevant compounds.For example,enynecarbinamine-containing natural product Dynemicin A and its triacetate are potent antibacterial and anticancer agents.To date,there are three major methods for synthesis of these important compounds.Put it simply,they are the addition of terminal alkynes to imines,amination of propargylic esters and the transition-metal catalyzed three-component coupling of an aldehyde,alkyne and an amine.However,there are some shortcomings for these synthetic methods,such as the low reaction activity,high loading of catalyst and narrow scope of substrates.In recent years,our group have developed diphosphine–rhodium complex with excellent activity and enantioselectivity in many asymmetric hydrogenation reactions.Herein,we speculate that the diphosphine-rhodium catalytic system should also be used for asymmetric hydrogenation of propargyl imine for synthesis of chiral propargylamines.(R,R)-Quinxo P*-Rh complex is used as a catalyst to screen(Z)-N’-(1-phenyl-3-(triisopropylsilyl)prop-2-yn-1-ylidene)benzohydrazide as the pre-model substrate.Several propargyl imine with different directing groups are subjected to the hydrogenation reaction catalyzed by a widely used rhodium complex bearing the P-stereogenic diphosphine ligand for improving enantioselectivity.We determined(Z)-4-nitro-N’-(1-phenyl-3-(triisopropylsilyl)prop-2-yn-1-ylidene)benzohydrazide as model substrate and the Josiphos as the optimal ligand.Different reaction conditions were further investigated to enforce catalytic hydrogenation effect.The optimal reaction conditions were listed in the following: at room temperature,using benzoic acid as a additive,DCM as reaction solvent,under 30 atm H2 pressure and 36 h for reaction time.With the optimal reaction conditions in hand,a series of propargyl imine was asymmetrically hydrogenated,directly affording chiral propargylamines in moderate yield and up to 94% ee.These products could be used in synthesis for chiral molecules of medicinal value.To sum up,we afford a highly effective way to obtain chiral propargylamine.