Palladium-Catalyzed Cross-couplings of Lithium Arylzincates with Aromatic Halides. Synthesis of Analogues of Isomeridianin G and Evaluation as GSK- 3 Inhibitors

International audienceSeveral analogues of Isomeridianin G have been synthesized using as a key step palladium-catalyzed crosscoupling reactions of lithium triorganozincates. The latter have been prepared by deprotonative lithiation followed by transmetalation using ZnCl2*TMEDA (1/3 equiv)

Synthesis of Unsymmetrical Heterobiaryls Using palladium-catalyzed cross-coupling reactions of lithium organozincates

International audienceSeveral unsymmetrical heterobiaryls have been synthesized through palladium-catalyzed cross-coupling reactions of lithium triorganozincates. The latter have been prepared by deprotonative lithiation followed by transmetalation using non hygroscopic ZnCl2*TMEDA (1/3 equiv)

Deprotonative metalation of five-membered aromatic heterocycles using mixed lithium-zinc species

International audienceDeprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc protected indole and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl2*TMEDA (0.5 equiv) and lithium 2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature was described. The reaction was evidenced by trapping with iodine, regioselectively giving the expected functionalized derivatives in 52 to 73% yields. A mixture of mono- and disubstituted derivatives was obtained starting from thiazole. Cross-coupling reactions of 2-metalated benzo[b]thiophene and benzo[b]furan with heteroaromatic chlorides proved possible under palladium catalysis. A reaction pathway where the lithium amide and zinc diamide present in solution behave synergically was proposed for the deprotonation reaction, taking account of NMR and DFT studies carried out on the basic mixture

Combinaison lithium-zinc pour la fonctionnalisation d'hétérocycles aromatiques (application à la synthèse d'analogues d'isoméridianines)

Le principal but de ce travail a été de mettre en évidence le potentiel synthétique de nouvelles combinaisons lithium-zinc. Après avoir identifié une nouvelle base lithium-zinc chimiosélective et efficace, nous avons exploré en série hétéroaromatique son aptitude à déprotoner. Les exemples de métallation présentés ont mis en évidence la diversité des hétérocycles déprotonés, la relative stabilité des espèces organométalliques formées et les différents paramètres intervenant lors de la déprotonation. Suite à ces études, un nouveau mécanisme réactionnel a été proposé. Une méthode de couplage de type Negishi a alors été développée afin d élargir les possibilités de fonctionnalisation des zincates hétérocycliques. Des structures biaryliques ont ainsi été obtenues. Les méthodes développées précédemment ont ensuite été utilisées pour effectuer des synthèses convergentes et des modulations structurales de cibles d'intérêt biologique. Divers analogues des isoméridianines ont ainsi été synthétisés dans le but d améliorer leur affinité pour GSK-3b, kinase impliquée dans la maladie d Alzheimer.The main purpose of this work was to highlight the synthetic potential of new lithium-zinc combinations. After identifying a new chemoselective and efficient lithium-zinc base, its ability to deprotonate was explored in aromatic heterocycles series. The different examples of metalation highlighted the diversity of heterocycles that may be deprotonated, the relative stability of the organometallic species formed, and the various parameters involved in the deprotonation. Following these studies, a new reaction mechanism was proposed. We then set up a method for Negishi-like cross-coupling to expand opportunities for functionalization of heterocyclic zincates. Several unsymmetrical heterobiaryls have been synthesized by this way. The previously developed methods were then used to perform convergent syntheses and structural modulations of targets with potential bioactivity. Some isomeridianine analogues were synthesized in order to improve their affinity for GSK-3b, kinase involved in Alzheimer's disease.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Lithium-mediated zincation of pyrazine, pyridazine, pyrimidine, and quinoxaline.

International audienceDeprotonation of pyrazine, pyridazine, pyrimidine, and quinoxaline using an in situ mixture of ZnCl2.TMEDA (0.5 equiv) and LiTMP (1.5 equiv) was studied. Pyrazine and pyrimidine were deprotonated in THF at room temperature, a result evidenced by trapping with I2. The competitive formation of dimer observed in net hexane was reduced by using cosolvents (TMEDA or THF). Starting from quinoxaline, the dimer formation took place in THF also, and mixtures of mono- and diiodides were obtained whatever the solvent and conditions used. A similar competitive formation of a diiodide was noted with pyridazine; the use of THF at reflux temperature nevertheless afforded the 3-iodo derivative in good yield

Investigations on interactions between titanium alkoxides and alpha,omega-dihydroxy PDMS by a combination of rheology and spectroscopy

International audienceThe phenomena involved in the reactions between alpha-omega-dihydroxy PDMS and titanium tetraalkoxides, Ti(OR)(4), were investigated by a combination of rheology and spectroscopy (NMR, IR). The increase of viscosity observed mainly originates from a linear chain extension of PDMS chains by formation of Ti-O-Si bonds. This is mainly related to an apparent functionality of 2 of Ti(OR)(4). The products formed evolve with time and are sensitive to hydrolysis due to the poor stability of Ti-O Si bonds. The precise understanding of the reactions involved raises interesting perspectives for the crosslinking of alpha-omega-dihydroxy PDMS and Si(OR)(4) derivatives using titanium tetraalkoxide based catalysts

Ligand-Activated Lithium-Mediated Zincation of N-Phenylpyrrole

International audienceMetalation of N-phenylpyrrole using an in situ mixture of ZnCl2*TMEDA (0.5 equiv) and LiTMP (1.5 equiv) was optimized. The reaction carried out at rt in THF resulted in incomplete metalation (56% conversion) and selectivity (mixture of 2-iodo and 2,2'-diiodo derivatives in a 86/14 ratio after trapping with iodine). Using DEE, toluene or hexane instead of THF, low conversions of 17, 38 or 23% were observed, respectively, but the formation of the diiodide was avoided. When hexane was used as solvent, strong lithium-complexing ligands such as 12-crown-4 and DMPU inhibited the reaction whereas more (hemi)labile ligands (TMEDA > THF ~ DME) favored it. This result shows that a temporary accessibility of lithium to interact with the rest of the base and/or the substrate is a prerequisite for an efficient metalation. A 75% yield of 2-iodo-N-phenylpyrrole was obtained after reaction with the base in the presence of 5 equiv of TMEDA for 2 h at rt, and subsequent trapping with iodine. Replacement of the spare TMP by a less expensive butyl group was attempted with success