December 2024

The selective functionalization of C–F bonds in trifluoromethylated arenes (ArCF3) is essential due to the extensive use of fluorinated compounds in pharmaceuticals, agrochemicals, and materials science, alongside emerging regulatory restrictions on trifluoromethyl groups. Here, we report a hybrid palladium-catalyzed strategy for the selective defluorination and functionalization of ArCF3, featuring intermolecular carboamination of linear conjugated dienes or defluorinative cross-coupling with nonactivated alkenes. This methodology enables the 1,4-addition of dienes with exclusive E-selectivity or the defluoroalkylation of (trifluoromethyl)arenes, providing efficient routes to difluoromethylated compounds and addressing key challenges in synthetic fluorine chemistry.

Theaflavins (TFs) contribute greatly to the color and flavor of black tea, and have various bioactivities beneficial to human health. This research compared the activity for TF production from tea polyphenols of recombinant polyphenol oxidase (Malus domestica, GenBank login number LT718523.1, MdPPO2) with that of commercial polyphenol oxidase (Agaricus bisporus, AbPPO) in both free and immobilized forms. Enzyme assays by LC-MS revealed that the production of TFs by the commercial enzyme AbPPO was almost five times as high as that of free recombinant MdPPO2. When immobilized on mesoporous silica, however, the activity of recombinant MdPPO2 increased significantly, whereas AbPPO almost lost its activity. In terms of the relative enzyme activity, the immobilized recombinant MdPPO2 had the highest relative enzyme activity, which was more than six times higher than that of free AbPPO. Among the TFs that were produced, TF3 was the most abundant, followed by TF2a, TF1, and TF2b.

The synthesis of bis(pyrrolo[2,1-a]isoquinolinyl)methanes was achieved through TfOH-catalyzed sequential Friedel–Crafts alkylation of pyrrolo[2,1-a]isoquinoline and aldehyde. A series of highly functionalized bis(pyrrolo[2,1-a]isoquinolinyl)methane derivatives can be obtained in acceptable to excellent yields (11 examples, up to 96% yield). Interestingly, deformylation was observed when treating pyrrolo[2,1-a]isoquinoline-derived aldehyde and indole under the current reaction conditions. Furthermore, the replacement of aldehyde with isatin resulted in the formation of methylene-bridged dimeric pyrrolo[2,1-a]isoquinoline.

A pyrimidinethione candidate carrying pyrazole and thiophene scaffolds was produced by a Biginelli cyclocondensation reaction of a pyrazolecarbaldehyde with pentan-2,4-dione and thiourea. To create some heteroannulated thiazolopyrimidines, the pyrimidinethione was subjected to cyclocondensation reactions with ethyl chloroacetate, 1,2-dibromoethane, chloroacetonitrile, and oxalyl chloride. A DFT simulation was performed for a frontier-orbital analysis to determine the molecular geometry. Among the products, 6-acetyl-7-methyl-5-[1-phen­yl-3-(2-thienyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidine-2,3-dione displayed the highest softness and the lowest energy gap in the DFT calculations. Moreover, it had the highest electrophilicity index, suggesting possible biological impacts. The compounds obtained were evaluated against cell lines of breast adenocarcinoma (MCF7) and hepatocellular carcinoma (HepG2) as antiproliferative agents. A simulation of the molecular docking of our compounds with the epidermal growth factor receptor demonstrated the rationality of our design and identified the binding mode. A model pharmacokinetics analysis showed that the products have the expected and desirable drug-like and bioavailability properties.