Asymmetric Hydrogenation Of Nitroquinolines And Quinolinamines

Although much progress has been achieved in the asymmetric hydrogenation of aromatic compounds, there is little information available in literature about the asymmetric hydrogenation of aromatic nitro compounds and aromatic amines. In this dissertation, asymmetric hydrogenation of3-nitroquinolines and quinolin-3-amines has been studied.Firstly, with chiral phosphoric acid as catalyst and1,4-dihydropyridine as hydrogen source, a highly efficient asymmetric transfer hydrogenation of3-nitroquinolines has been successfully developed, providing a series of valuable enantiopure cyclic nitro compounds with up to99%ee. Preliminary mechanistic studies indicate that the1,4-H addition may be the initial step in the reaction. The reaction is initiated via1,4-H addition to give the partially hydrogenated intermediate,3-nitro-1,4-dihydroquinoline, followed by isomerization to imines in the presence of chiral phosphoric acid, which then undergoes rapid further1,2-H addition to deliver the desired product. In addition, this methodology was also employed as the key step for the asymmetric synthesis of a substrate P antagonist.Secondly, an efficient [Ir(COD)Cl]2/DifluorPhos/I2catalyst system has been employed in the asymmetric hydrogenation of quinolin-3-amines, providing a series of chiral exocyclic amines with up to99%yield and94%ee. This is the first example on the highly enantioselective asymmetric hydrogenation of aromatic amines. The key factor in the successful asymmetric hydrogenation is the introduction of phthaloyl group to the amino group:1) It can suppress the strong coordination ability of the substrate and the corresponding reduced product to catalyst.2) It can activate the substrate through decreasing the electron density of the aromatic rings.3) It can improve the diastereoselectivity by inhibition of side reaction pathway.Subsequently, an efficient asymmetric hydrogenation of quinolin-3-amines has been developed with palladium catalyst generated in situ from Pd(OCOCF3)2and an axially chiral bisphosphine ligand with trifluoroacetic acid as additive. The corresponding chiral exocyclic amines were given with up to97%yield and90%ee. This reaction broadens the application of palladium catalysts in asymmetric hydrogenation.Finally, an asymmetric transfer hydrogenation of2-aryl substituted quinolin-3-amines was developed using chiral phosphoric acid as catalyst and Hantzsch esters as hydrogen source, giving the chiral exocyclic amines with up to99%ee. Our previously developed strategies on the asymmetric hydrogenation of quinolin-3-amines catalyzed by iridium or palladium could catalyze the hydrogenation of2-alkyl substituted substrates with high enantioselectivities, however, for2-phenyl substituted substrate, both of them were failed to give high ee values. Thus, the new method is a very good complement to our previous works. Preliminary mechanistic studies indicate that the reaction mainly proceeds via an endocyclic imine intermediate.