Asymmetric Ring-Closing Aminoalkylative Amination Of Unsaturated Hydrocarbons Directed By Cyclopalladated Complex

The transition metal-catalyzed asymmetric annulative carboamination of unsaturated hydrocarbons forges a new C-C bond and a new C-N bond in a single reaction while constructing chiral N-heterocycles,and therefore features the advantage of high step-economy and is an efficient way to synthesize chiral N-heterocycles.Among the various carboamination reactions known,the reaction catalyzed by palladium is of great interest for featuring low catalyst loading,mild reaction conditions,good functional-group compatibility,and easy adjustment of catalytic performance.However,despite the considerable progress achieved in this field,the synthesis of medium-and macro-sized chiral N-heterocycles remains elusive;moreover,the reported reactions largely rely on the formation of stable aryl-or alkenylmetal species,and catalytic reactions directed by alkyl metal intermediates are currently difficult to accomplish due to the instability of such metal intermediates.In this thesis,directed by a unique cyclopalladated complex(Huang-complex)as the leading complex,a series of novel asymmetric ring-closing carboamination reactions of unsaturated hydrocarbons have been developed through the design of chiral ligands,and a variety of functionalized chiral N-heterocycles have been synthesized efficiently.1.A highly enantioselective ring-closing aminomethylamination of aminodienes by using modified Trost ligands was developed.Under the optimal reaction conditions,a series of enantiomer-enriched 5-to 16-membered β-aminoallylated N-heterocycles were obtained with up to 95%yield and 98%ee in the presence of 2 mol%[Pd(allyl)(CH3CN)2]OTf and 2.2 mol%chiral ligands in DCE at 0 ℃ for 12 hours.Moreover,with the chiral product as the starting material,the formal synthesis of the natural product(+)-(8S,13R)-cyclocelabenzine was realized,highlighting the practicability of this reaction.2.Taking advantage of the unique properties of the cyclopalladated complex,a new C-N bond metathesis of tertiary amine was established and applied to the asymmetric ring-closing aminomethylamination of allyl aminodienes.Under the optimal reaction conditions,a series of chiral 5-to 10-membered β-aminoallylated N-heterocycles were obtained with up to 89%yield and 90%ee in the presence of 5 mol%[Pd(allyl)(CH3CN)2]OTf,5.5 mol%chiral ligands and 20 mol%1-NpCO2H as additive in PhCl at 0℃ for 12 hours.3.A palladium-catalyzed asymmetric ring-closing aminomethylamination of aminoenynes by using modified chiral phosphoramidite ligands was developed.Under the optimized reaction conditions,a series of chiral exocyclic allenic amines bearing 6 or 7-membered N-heterocycles were obtained with up to 78%yield and 93%ee in the presence of 2.5 mol%[Pd(π-cinnamyl)Cl]2,5.5 mol%chiral phosphoramidite ligands and 15 mol%AgClO4 in CH2Cl2 at-10℃ for 30 h.It is worth pointing out that this represents the first palladium-catalyzed asymmetric 1,4-carboamination reaction of unactivated enynes.Not only can the reaction be scaled up at the gram-scale,but also can the resulting chiral exocyclic allenic amines be transformed into high value-added chiral spirodiamines via axial-to-central chirality transfer.By exploiting this strategy,the facile synthesis of a spirodiamine-containing molecule exhibiting good activity in inhibition against Janus kinases was achieved.4.Based on the strategy for the in situ generation of cyclopalladated complex from amine and aldehyde,a palladium-catalyzed three-component ring-closing carboamination reaction of aminoenynes/aldehydes/primary or secondary amines was developed.Under the optimal reaction conditions,a series of exocyclic allenic amines were obtained with 21-88%yields in the presence of 5 mol%[Pd(Xantphos)(CH3CN)2](OTf)2 in CH2Cl2 at 80℃ for 12 h.In particular,the in-situ generated alkyl-palladium species could be stabilized by ligation of the palladium center with the adjacent amino group,thus making this reaction amenable to aliphatic aldehydes.The palladium-catalyzed asymmetric ring-closing aminoalkylative amination reaction with aromatic amines as nucleophiles was also realized via ligand rational design.Under the optimal reaction conditions,a series of chiral exocyclic allenic amines were obtained with up to 85%yield and 99%ee in the presence of 2.5 mol%[Pd(π-cinnamyl)Cl]2,11 mol%chiral phosphoramidite ligands and 8 mol%AgClO4 in CH2Cl2 at-30℃ for 24 h.Moreover,a two-step one-pot method was successfully employed for the efficient synthesis of chiral spirodiamines by utilizing primary aromatic amine as the reactant.5.Based on the strategy for the in situ generation of cyclopalladated complex from amine and aldehyde,a palladium-catalyzed stereoselective cyclization of aminoenynes with aldehydes and boronic acids was developed.Under the optimal reaction conditions,a series of exocyclic conjugated dienes bearing 5-to 8-membered saturated N-heterocycles were obtained with up to 94%yield and excellent stereo-selectivity in the presence of 1 mol%Pd(PPh3)4 and Na2CO3 in DME at 80℃for 6 hours.Various alkyl aldehydes,aryl aldehydes and unsaturated aldehydes are compatible with this reaction thanks to the coordination of adjacent amino group on alkyl palladium.