A new synthesis of a group of O‐, S‐ and N‐heterocycles with a gem‐difluoro group in position β to the heteroatom has been developed, starting from easily accessible gem‐difluoro propargylic derivatives. This tandem process involves a base‐induced isomerization followed by an intramolecular 1,4 hetero‐Michael addition. This methodology is suitable for the preparation of five‐ and six‐membered heterocycles and it has been successfully applied to the synthesis of the 3,3‐difluoro analogues of (±)‐sedamine III, (±)‐allosedamine V, (±)‐norallosedamine II, and (±)‐norsedamine IV.

IntroductionNew fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflammatory effects in primary macrophages.MethodsThe synthesis of the designed molecules started from easily accessible and versatile gem-difluoro propargylic derivatives. The desired aromatic systems were obtained using Diels–Alder/aromatization sequences and this was followed by Pd-catalyzed coupling reactions and, when required, final functionalization steps. Both direct inhibitory effects on cyclooxygenase-1 or -2 activities, protein expression of cyclooxygenase-2 and nitric oxide synthase-II and the production of prostaglandin E2, the pro-inflammatory nitric oxide and interleukin-6 were evaluated in primary murine bone marrow-derived macrophages in response to lipopolysaccharide. Docking of the designed molecules in cyclooxygenase-1 or -2 was performed.ResultsOnly fluorinated compounds exerted anti-inflammatory activities by lowering the secretion of interleukin-6, nitric oxide, and prostaglandin E2, and decreasing the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in mouse primary macrophages exposed to lipopolysaccharide, as well as cyclooxygenase activity for some inhibitors with different efficiencies depending on the R-groups. Docking observation suggested an inhibitory role of cyclooxygenase-1 or -2 for compounds A3, A4 and A5 in addition to their capacity to inhibit nitrite, interleukin-6, and nitric oxide synthase-II and cyclooxygenase-2 expression.ConclusionThe new fluorinated diaryl ethers and bisarylic ketones have anti-inflammatory effects in macrophages. These fluorinated compounds have improved potential anti-inflammatory properties due to the fluorine residues in the bioactive molecules.

Using an aerobic oxidative coupling, different new imidazo[1,2-a]-N-heterocycles with gem-difluroroalkyl side chains have been prepared in fair yields by the reaction of gem-difluoroenones with aminopyridines, -pyrimidines and -pyridazines. Condensed heterocycles of this type play an important role as key core structures of various bioactive compounds. Further, starting with a chloroimidazopyridazine derivative, Pd-catalyzed coupling reactions as well as nucleophilic substitutions have been performed successfully in order to increase the molecular diversity.

International audienceStarting from easily accessible propargylic fluorides an intramolecular oxa-Michael addition affords, in good yields, new gem-difluorodihydrobenzofurans bearing an electrophilic double bond in position 2. On these intermediates nucleophilic additions and Diels-Alder reactions have been performed affording functionalized fluorinated dihydrobenzofurans. On the other hand, Pd-catalyzed defluorinations give the corresponding fluorine containing benzofurans

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