Direct access to benzo-fused nine-membered heterocyclic alkenes with a trifluoromethyl carbinol moiety was achieved via a palladium-catalysis.

The halogen-bond donors FBSM-I and FBDT-I, which contain an sp3-hybridized carbon–iodine (Csp3 –I) moiety, were designed and synthesized. The highly electron-withdrawing nature of the fluorobissulfonyl-methane scaffold leads to the generation of σ-holes on the surface of the iodine atoms in FBSM-I and FBDT-I. Mukaiyama aldol reactions and hydrogen-transfer reductions are efficiently catalyzed by FBSM-I and FBDT-I under neutral and mild reaction conditions. The driving force for these transformations should be the halogen bonding induced by FBSM-I and FBDT-I, which was confirmed by DFT calculations, single-crystal X-ray diffraction analyses, and NMR titrations.

Fluoro-functionalized heterocycles and mediumsized heterocycles are both attractive skeletons in medicinal chemistry. However, the construction of medium-sized fluorofunctionalized heterocycles remains unexplored. Their synthesis represents a formidable challenge due to the unfavorable entropic and enthalpic factors that arise from medium-sized rings and the unexpected properties induced by fluorinated groups. Here, we describe an efficient method for the preparation of highly functionalized gem-difluoromethylene N-heterocyclic lactones with 9-to 11-membered rings in a sequential CN-bond-cleaving ring-expansion process using difluoro-oxindoles, various zwitterion precursors, and a Pd catalyst. This sequential CN-cleaving expansion process was extended to synthesize nonfluorinated, medium-sized heterocycles with an α-keto-lactone moiety using isatin derivatives. Additionally, monofluorinated and nonfluorinated oxindoles were transformed into the corresponding medium-sized heterocyclic lactones using this protocol. The key for this transformation is the cleavage of the unreactive amide CN bond, which is smartly activated by the incorporation of two neighboring electron-withdrawing groups assisted with the nucleophilic attack of a Pdcoordinated zwitterion. The site-selective functionalization of a series of heterocyclic products was demonstrated to show their synthetic utility. Mechanistic details of the sequential cleavage/expansion process were proposed based on liquid chromatography− mass spectrometry (LC−MS) analyses.

The two enantiomers of trifluoromethyl‐benzo[c][1,5]oxazonines, (R)‐4 and (S)‐4, can be selectively accessed with high enantiopurity by the Pd‐catalyzed ring‐expansion reaction of trifluoromethyl‐benzo[d][1,3]oxazinones (1) with vinyl ethylene carbonates (3) using one antipode of a chiral ligand. Initially, the reaction proceeds by a double decarboxylative ring‐expansion with kinetic resolution of 1 in the presence of a Pd‐catalyst/chiral ligand to provide (R)‐4 with high enantiopurity. At the same time, the nonreactive antipode of 1, (S)‐1, which was recovered with an impeccable s factor of up to 713 and an ideal chemical yield, was transferred into the antipode of the products, (S)‐4, with high enantiopurity by a second run of the Pd‐catalyzed double decarboxylation reaction, but this time without any chiral auxiliary. Thus, both antipodes of the chiral trifluoromethyl heterocycles 4 can be obtained in excellent enantiopurity using only a single antipode of the chiral catalyst.

The enantioselective ethoxycarbonyldifluoromethylation of Morita−Baylis−Hillman (MBH) fluorides with Me 3 SiCF 2 CO 2 Et under organocatalysis is described. Moderately functionalized chiral gem-difluoromethylene compounds with a stereogenic "C-CF 2 -C*" unit were synthesized in high yields with high enantioselectivities. The initial C−F bond activation is assisted by the silicon atom via a dual S N 2′-S N 2′ stepwise pathway. Dynamic kinetic resolution of the MBH-fluorides explained the high yields and high ee's of the products. The method was extended to the enantioselective introduction of "Het-CF 2 " units.