Studies On Nickel-catalyzed Enantioselective [2+2+2] Cycloaddition Reactions Involving Nitriles

Chiral pyridine is an important heterocyclic compound.Transmetal-catalyzed[2+2+2]cycloaddition is an efficient method for the straightforward construction of pyridine rings from readily available alkynes and nitriles.Although this type of reaction was discovered 50 years ago,it’s application in the construction of multi-substituted chiral pyridines.It is of great significance to design and develop transition-metal-catalyzed asymmetric[2+2+2]cycloaddition reactions involving nitriles to achieve enantioselective assembly of polysubstituted chiral pyridines and their derivatives.This thesis studied the chirality induction of prochiral disubstituted malononitriles via hetero-oxidetive metallation of nickel catalyst,alkyne and nitrile group,enabling construction of chiral center-containing pyridine derivatives with high enantioselectivity.In the first part,the substrate scope and mechanism of a nickel-catalyzed desymmetrizing[2+2+2]cycloaddition of alkynyl-substituted malononitrile and alkynes were investigated.The substrate scope was successfully extended to terminal alkynes,and 2,3,4,6-tetrasubstituted pyridines were accessed with excellent regioselectivity and enantioselectivity.The mechanistic studies ³¹P NMR experiments and DFT theoretical calculations revealed that Zn Br₂ can 1)promote the complexation of phosphine ligands and nickel precursors,and 2)accelerate the hetero-oxidative cyclometallation.The chirality control model and the regioselectivity model of the reaction were also developed,which provided a theoretical foundation for the subsequent synthesis of spiropyridines.In the second part,a nickel-catalyzed double[2+2+2]cycloaddition of bisalkynyl-substituted malononitriles with alkynes was developed.The desymmetrization of malononitrile was achieved by azametallation of alkynes,cyano groups and nickel complex,leading the synthesis of C₂-symmetric spiropyridines with excellent enantioselectivity（>99%ee）and regioselectivity>20:1（for terminal alkynes）.We The application was show cased by the synthesis of polyoxazolines and thioureas based on the spiropyridines.In the third part,a kinetic resolution of alkyne substituted nitriles by a nickel-catalyzed[2+2+2]cycloaddition was developed.C₁-Symmetric chiral spiropyridines were obtained in 32-55%yield with 90-99%ee.The unreacted substrates was recovered in 42-55%yield with 86-99%ee.The kinetic resolution reaction is found zeroth order dependence（krel>199）on the nitrile as revealed substrate by kinetic analye.