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

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.

Visible-Light-Induced Palladium-Catalyzed Selective Defluoroarylation of Trifluoromethylarenes with Arylboronic Acids.

Selective functionalization of inactive C(sp3)-F bonds to prepare medicinally interesting aryldifluoromethylated compounds remains challenging. One promising route is the transition-metal-catalyzed cross-coupling through oxidative addition of the C(sp3)-F bond in trifluoromethylarenes (ArCF3), which are ideal precursors for this process due to their ready availability and low cost. Here, we report an unprecedented excited-state palladium catalysis strategy for selective defluoroarylation of trifluoromethylarenes with arylboronic acids. This visible-light-induced palladium-catalyzed cross-coupling proceeds under mild reaction conditions and allows transformation of a variety of arylboronic acids and ArCF3. Preliminary mechanistic studies reveal that the oxidative addition of the C(sp3)-F bond in ArCF3 to excited-state palladium(0) via a single electron transfer pathway is responsible for the C(sp3)-F bond activation.

Stereoselective Functionalization of Racemic Cyclopropylzinc Reagents via Enantiodivergent Relay Coupling.

Efficient construction of optically pure molecules from readily available starting materials in a simple manner is an ongoing goal in asymmetric synthesis. As a straightforward route, transition-metal-catalyzed enantioconvergent coupling between widely available secondary alkyl electrophiles and organometallic nucleophiles has emerged as a powerful strategy to construct chiral center(s). However, the scope of racemic secondary alkylmetallic nucleophiles for this coupling remains limited in specific substrates because of the difficulties in stereoselective formation of the key alkylmetal intermediates. Here, we report an enantiodivergent strategy to efficiently achieve an array of synthetically useful chiral cyclopropanes, including chiral fluoroalkylated cyclopropanes and enantiomerically enriched cyclopropanes with chiral side chains, from racemic cyclopropylzinc reagents. This strategy relies on a one-pot, two-step enantiodivergent relay coupling process of the racemic cis-cyclopropylzinc reagents with two different electrophiles, which involves kinetic resolution of racemic cis-cyclopropylzinc reagents through a nickel-catalyzed enantioselective coupling with alkyl electrophiles, followed by a stereospecific relay coupling of the remaining enantiomeric cyclopropylzinc reagent with various electrophiles, to produce two types of functionalized chiral cyclopropanes with opposite configurations on the cyclopropane ring. These chiral cyclopropanes are versatile synthons for diverse transformations, rendering this strategy effective for obtaining structurally diversified molecules of medicinal interest.