Chemo‐, Stereo‐ and Regioselective Fluoroallylation/Annulation of Hydrazones with gem‐Difluorocyclopropanes via Tunable Palladium/NHC Catalysis

Abstract

Defluorinative manipulation of polyfluorinated molecules has shown great promise due to its granting of synthetic versatility to inert CÀ F bonds. The development of chemo-, stereo-and regioselective strategies to realize highly efficient formation of either the linear/branched or E/Z products from gem-difluorocyclopropanes (gem-F 2 CPs) is a challenging task. Herein, we have realized palladium/NHC-catalyzed fluoroallylation/annulation of hydrazones with gem-F 2 CPs that incorporate the hydrazone N 2 moiety into the products. The thermodynamically unstable fluorinated E-allylation products with aryl ketone hydrazones were obtained for the first time, while the di-alkyl ketone hydrazones yielded the monofluorinated products with branched selectivity under similar reaction conditions. With aldehyde hydrazones, two kinds of pyrazoles were obtained via a defluorinative allylation/annulation cascade, in which different carbon atoms of gem-F 2 CPs could be incorporated into the pyrazole rings regiospecifically. DFT calculations revealed that the divergent selectivity was kinetically controlled and the final CÀ C bond formation proceeded through a 7-membered TS.

Pd-IHept-Catalyzed Ring-Opening of gem-Difluorocyclopropanes with Malonates Via Selective C–C Bond Cleavage: Synthesis of Monofluoroalkenes

“…The Pd-PEPPSI catalysts were synthesized according to the reported literature . The gem -difluorocyclopropanes were synthesized according to the reported literature. , All other reagents were purchased from Alfa, Aldrich, TCI, Energy, Innochem, and Sinocompound Catalysts and used without further purification. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments.…”

“…Since then, continuous efforts have been made to expand the substrate scope by Fu, Gong, Xia, and other research groups (Scheme b) . In 2021, our group realized the Pd-catalyzed regioselective alkylation of gem -F 2 CPs with unstabilized ketones, in which an inner-sphere 3,3′-reductive elimination of the enolate-Pd-fluoroallylic intermediate was proposed to provide the α-fluoroalkene products (Scheme c).…”

A DFT study of NHC-catalyzed reactions of [3+3] annulations of 2-bromoenals and thioamides: mechanisms and regio- and stereoselectivities

“…N-heterocyclic carbenes (NHCs), generally prepared by deprotonating imidazolium, azolium or thiazolium salts (Scheme 1), have garnered considerable attention over the past few decades owing to their interesting properties. 11,12 In addition to their utilization as effective ligands for organometallic catalysts, 13–17 NHCs also have application as organocatalysts. 18–22 The essence of NHC-catalyzed umpolung reactions lies in that the employed NHCs are able to convert the electrophiles (such as aldehydes and enals) to nucleophilic intermediates via nucleophilic attack of the NHCs on the carbonyl group, and then the reactive intermediates couple with other electrophiles, offering great potential for a variety of transformations, such as C–C 23–25 /C–X (X = O, N etc. )…”

Ligand-controlled regioselective cascade C–C/C–F cleavage/annulation of gem-DFCPs: a divergent synthesis of pyrroles

“…9 Very recently, they realized a divergent synthesis of pyrazoles based on the annulation of gem -DFCPs with different kinds of aldehyde hydrazones. 10 Compared with the well-developed cross-coupling reaction of gem -DFCPs with one-fold C–F cleavage, examples of annulation reaction with two-fold C–F cleavage are still rare. In light of the potential utility of the pyrrole skeleton, 11 we envisioned whether an efficient synthesis of pyrroles could be achieved using a cascade ring-opening/defluorinative annulation of gem -DFCPs.…”