•α,α-difluorobenzoyl oxygen heterocycles were synthesized via the radical cyclization of 2-iodo-2,2-difluoroacetophenone.•The reactions proceeded to give the cyclization products directly with high yields.•The different reaction conditions was ascribed to the different nucleophilic efficiency between carboxyl and hydroxyl groups.•The addition of base 2,6-lutidine is essential for efficient synthesis of α,α-difluorobenzoyl cyclic ethers.A convenient and facile method for the direct synthesis of α,α-difluorobenzoyl lactones or cyclic ethers via the radical cyclization reaction of 2-iodo-2,2-difluoroacetophenone with unsaturated acids or alcohols was reported.Download high-res image (84KB)Download full-size image

Lithium triethylborohydride was found to promote the generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones, and applied to the synthesis of polyfluorinated β-hydroxy ketones via self-condensation or aldol reaction. The reaction indicates an unprecedented utilization of lithium triethylborohydride and provides novel access to the generation of α,α-difluoroenolates.

Lithium triethylborohydride was found to promote the generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones, and applied to the synthesis of polyfluorinated β-hydroxy ketones via self-condensation or aldol reaction. The reaction indicates an unprecedented utilization of lithium triethylborohydride and provides novel access to the generation of α,α-difluoroenolates.

Feasible and effective peptide ligand-modified solid lipid nanoparticles (SLNs) have been designed to improve the oral bioavailability of atorvastatin calcium (ATC). In the present work, the peptide ligand-modified SLNs loaded with ATC, namely ATC CSK-SLNs, were prepared by coupling the peptide ligand CSKSSDYQC (CSK), which showed affinity with goblet cells, to stearic acid. The physicochemical properties of the SLNs were characterized by TEM, DSC and FT-IR, which unravelled the transformation of ATC to an amorphous or molecular state from the native crystalline form. Compared with unmodified SLNs, the CSK-SLNs exhibited a more efficient cellular uptake across the Caco-2/HT29 co-cultured cell monolayer as evidenced by confocal laser microscopy. Following absorption, the mechanisms were studied using a modified in situ perfusion method in rats, which showed the segment-dependent absorption characteristics of ATC, ATC SLNs as well as ATC CSK-SLNs. The Ka (0.076 ± 0.23 min−1) and Papp (0.011 ± 0.63 cm min−1) values of the ATC CSK-SLNs were raised 2.97-fold and 2.99-fold in comparison with those of the ATC solution, implying that CSK peptide modification enhances the permeation of drugs across the epithelium. In conclusion, our results demonstrated that CSK-modified SLNs could be potential carriers for the transport of drugs across intestinal barriers.

Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure–activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.

A series of novel oxazolidinone derivatives bearing fluoroalkyl-substituted pyrazole as the C-ring structure were designed, synthesized and evaluated for their antibacterial activity against six Gram-positive bacterial pathogens. Most of the target compounds have good antibacterial activity. Especially, compounds 13f, 13i and 13l show excellent activity comparable to linezolid.

A convenient and efficient approach for difluoroalkyl-containing γ-butyrolactones via the radical addition reaction of iododifluoromethyl ketones with 4-pentenoic acids initiated by AIBN in CH3CN at 60 °C was reported. Various difluoroalkyl-containing δ-valerolactones were also synthesized under this reaction conditions.A convenient and efficient approach for difluoroalkyl-containing γ-butyrolactones via the radical addition reaction of iododifluoromethyl ketones with 4-pentenoic acids initiated by AIBN in CH3CN at 60 °C was reported. Various difluoroalkyl-containing δ-valerolactones were also synthesized under this reaction conditions.

A series of 5-difluoromethyl-isoxazoles 2 were prepared, and their regioselective nucleophilic addition to aldehydes was investigated. It was found that the nucleophilic difluoromethylation of aldehydes with 5-difluoromethyl-isoxazoles could be efficiently and uniquely achieved in the presence of LDA as a base that provides a large steric hindrance. In contrast, 3,4,5-trisubstituted 5-difluoromethyl isoxazoles were alternatively afforded as the sole product in moderate yields when n-BuLi was used as the base.Graphical abstractHighlights► 5-Difluoromethyl-isoxazoles were applied as efficient nucleophilic reagents. ► The proper use of base play an important role. ► Aldehydes could be difluoromethylated by treatment of LDA as a base. ► Isoxazoles merit superior atom-economical feature in fluoroalkylation reactions.

The crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile was obtained and determined by X-ray crystallography. The reaction mechanism of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl compounds was further proposed.

A series of γ,γ-difluoro-β-hydroxy-δ-lactones 1 were efficiently synthesized as new precursors of HMG-CoA reductase inhibitor in one pot by treatment of readily prepared gem-difluoromethylenated acetonides 3 with trifluoroacetic acid. Contrarily, acetonides 3 could be transformed to the γ,γ-gem-difluoromethylenated α,β-unsaturated δ-lactones 2 through hydrolyzation and lactonization in refluxing toluene.Graphical abstractA series of γ,γ-difluoro-β-hydroxy-δ-lactones 1 was efficiently synthesized as new precursors of HMG-CoA reductase inhibitor in one pot by treatment of readily prepared gem-difluoromethylenated acetonides 3 with trifluoroacetic acid. Contrarily, acetonides 3 could be transformed to the γ,γ-gem-difluoromethylenated α,β-unsaturated δ-lactones 2 through hydrolyzation and lactonization in refluxing toluene.Highlights► CF2 group was first introduced to β-hydroxy δ-lactones at the γ-position. ► β-Hydroxy δ-lactones were synthesized as HMG-CoA reductase inhibitor precursors. ► Acetonides underwent cyclization to afford β-hydroxy δ-lactones promoted by TFA. ► Acetonides were transferred to α,β-unsaturated δ-lactones in refluxing toluene.

•A phosphine-catalyzed [3 + 2] annulation of N-aryl fluorinated imines with allenoates is reported. A series of fluorinated pyrrolines is obtained in moderate yield which are further transformed to fluorinated pyrroles via dehydro-aromatization by DDQ in high to excellent yield.•The reaction mechanism is also discussed.A phosphine-catalyzed [3 + 2] annulation of N-aryl fluorinated imines with allenoates is reported. A series of fluorinated pyrrolines is obtained in moderate yield, which are further transformed to fluorinated pyrroles via dehydro-aromatization by DDQ in high to excellent yield. The reaction mechanism is also discussed.A phosphine-catalyzed [3 + 2] annulation of N-aryl fluorinated imines with allenoates is reported. A series of fluorinated pyrrolines is obtained in moderate yield, which are further transformed to fluorinated pyrroles via dehydro-aromatization by DDQ in high to excellent yield.