Studies On Reactions Of Difluoroenoxysilanes With Imines Or Alkenes

Difluoroenoxysilane is identified as a commonly used synthetic building block for the selective introduction of?,?-difluoroketone unit.To extend its synthetic application,a more practical Mukaiyama-Mannich reaction and a novel hydrodifluoroalkylation of simple alkenes are developed,which provide efficient access to value-added?-amino-or?-alkyl substituted?-difluoroalkylated ketones.The detailed research works are introduced as follows:1)A Ph₃PAuOTf catalyzed in-situ imine formation/Mannich sequence of N-Boc or N-Cbz protected?-amido sulfones with difluoroenoxysilanes is achieved,affording a series of structurally diverse?-amino-?-fluorinated ketones.The practicability of this protocol is demonstrated by the fact that it avoids the pre-preparation of aldimines,and the protecting group of the products can be easily removed under mild conditions.Further study reveals that the sequence also proceeds smoothly under air without the use of any catalyst,just by prolonging the reaction time and increasing the amount of difluoroenoxysilanes.Mechanistic research suggests that the in-situ generated PhSO₂TMS or PhSO₂H from the imine formation step can serve as a promoter for the subsequent Mannich reaction.Moreover,an efficient Mukaiyama-Mannich reaction of unactivated ketimines with difluoroenoxysilanes is realized by using Sc?OTf?₃ as the catalyst,which provides a general method for the synthesis of?-amino-?-difluoroalkylated ketones bearing a tetrasubstituted carbon center.A new type of phosphine-phosphoramide ligands derived from chiral?-amino acids is developed and applied to the catalytic asymmetric variant,but unfortunately the results are not ideal.2)An unprecedent Markovnikov regioselective hydrodifluoroalkylation of simple alkenes is established.Under the catalysis of inexpensive and available Mg?ClO₄?₂?6H₂O,a variety of mono-,di-,tri-and tetrasubstituted alkenes are all workable,which allows the diversity-oriented synthesis of?-difluoromethylated ketones with a quaternary or tertiary carbon at the?-position that are otherwise difficult to access efficiently.The broad substrate scope,mild condition,simple operation,and the late-stage modification of natural products and drugs,as well as the gram-scale synthesis and the diversifying transformations of the products highlight the practicability of this protocol.Preliminary mechanistic studies reveal that Mg?ClO4?2?6H2O acts as a hidden Br?nsted acid catalyst,which gradually releasing HClO4 to catalyse the reaction,thereby avoiding the olefins dimerization or polymerization side reactions.The deuteration experiment suggests that the proton in this hydrodifluoroalkylation mainly originates from the crystal water of Mg?ClO₄?₂?6H₂O.