Regio- and enantioselective umpolung gem-difluoroallylation of hydrazones via palladium catalysis enabled by N-heterocyclic carbene ligand

Abstract

The enantioselective construction of C–CF2R (R: alkyl or fluoroalkyl) bonds has attracted the attention of synthetic chemists because of the importance of chiral fluorinated compounds in life and materials sciences. Catalytic asymmetric fluoroalkylation has mainly been realized under organocatalysis and Lewis acid catalysis, with substrates limited to carbonyl compounds. Few examples using transition-metal catalysis exist, owing to side reactions including decomposition and isomerization of fluoroalkylating reagents. Herein we report umpolung asymmetric difluoroallylation of hydrazones with 3-bromo-3,3-difluoropropene (BDFP) under palladium catalysis. Difluoroallylation products having quaternary chiral carbon centers are afforded in good yields with high α/γ- and enantioselectivities. The usefulness of the reaction products is demonstrated and an inner-sphere mechanism of the reaction is proposed. The use of chiral N-heterocyclic carbene as ligand is the key for the selectivities as well as the productivity of the reaction.

Pd/NHC-Controlled Regiodivergent Defluorinative Allylation of gem-Difluorocyclopropanes with Allylboronates

“…Considering the intrinsic affinity of heteroatom to Pd in the ambident nucleophiles, we focused the use of all-carbon allyl groups whose coordinational modes are easily tunable. Inspired by the elegant allyl–allyl cross-couplings reported by Echavarren, Morken, and Hou, we set out to develop a regiodivergent synthetic protocol for the defluorinative allylation of gem -difluorocyclopropanes. We envisioned capitalizing on the steric tunability of NHC ligands , to energetically discriminate between the regioisomeric transition states leading to branched and linear products (Scheme c).…”

Light-mediated catalytic enantioselective difluoroalkylation of β-ketoesters via phase-transfer catalysis

“…[4][5][6] To install difluoroalkyl moieties enantioselectively typically requires the use of transition metals either as photocatalysts or to provide a chiral environment with an enantiopure ligand. [7][8][9][10][11][12][13] In the context of difluoroalkyl radicals, their enantioselective incorporation into a molecule has been limited to two examples, but both require the use of transition metals. First, Lu and Xiao harnessed a chiral nickel Lewis acid catalyst with an iridium photocatalyst for the asymmetric difluoroalkylation of β-ketoesters (Fig.…”

Umpolung Reactivity of in Situ Derived Aryl Hydrazones: An Asymmetric Brønsted Acid Catalyzed Strategy to Access Fused Pyrazolidines

“…For instance, in 2012, the research groups of Vicario and Lassaletta distinctively showcased the first systematic alteration of these factors in N-monosubstituted hydrazones to investigate umpolung reactivity toward α,β-unsaturated aldehydes and diketones, respectively . Subsequently, Lassaletta and other research groups further explored the same reactivity of hydrazones with other electrophiles, including nitroalkenes. , All of these sophisticated approaches have been confined to the asymmetric synthesis of acyclic diazaene derivatives from pre-existing hydrazones (Scheme A-a).…”