关键词: 三氟甲基全碳季碳中心, 钯催化, 吲哚啉, Heck 反应, 三氟甲基

The construction of trifluoromethyl all-carbon quaternary centers is a significant challenge in organic synthesis. We report a palladium-catalyzed, interrupted Heck reaction that directly forges challenging allylic CF₃-all-carbon quaternary centers from trisubstituted-alkene with a CF₃ group. It provides the first general access to C3-functionalized indolines bearing an allylic CF₃-quaternary center. This method is highly selective, yielding exclusively the 5-exo-trig cyclized product and no 6-endo-trig isomers. Substrates bearing electron-donating or -withdrawing groups were compatible. This reaction tolerated a wide range of functional groups, including ester, nitro, halides (Cl, Br), ether, allyl, amine, amide, heterocycles. The N-protecting group in the substrate have an important effect on the reaction efficiency, in which acetyl group is the optimal choice. This reaction was sensitive for steric hindrance. When the ortho-bromo aniline in substrate 3 was replaced with an ortho-benzylamine, the regioselectivity was completely altered, yielding only the 7-endo-trig cyclization product 5 with no observed 6-exo-trig product. Further transformation of products was carried out. Unexpected deacylation-Pd-catalyzed C-N coupling product was obtained using strong base potassium tert-butoxide; instead, Pd-catalyzed Heck-coupling product was isolated using weaker Cs₂CO₃ as a base. Control experiments indicated that the diacylation occurred only in the presence of potassium tert-butoxide. Stochiometric reaction of 3a with Pd(PPh₃)₄ did give the oxidative addition palladium intermediate, instead, product 4a was obtained in 50% yield, which indicated that the rate of 5-exo intramolecular Heck cyclisation and subsequent β-H elimination is so fast that we did not isolate Ar-Pd-Br complex. Accordingly, added Pd(MeCN)₂Cl₂ (10 mol%), BINAP (10 mol%), Cs₂CO₃ (0.2 mmol) were introduced into an oven-dried Schlenk tube (10 mL) under N₂ atmosphere. Dried THF (2 mL) and (Z)-N-(2-bromophenyl)-N-(2-(trifluoromethyl)but-2-en-1-yl) acetamide (0.2 mmol) were added via syringe. The reaction mixture was stirred at 100 °C in oil bath for 12 h. The mixture was then cooled to room temperature, filtered with celite and washed with ethyl acetate. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE/EA = 10:1 to 5:1) to afford the desired products 4.

Key words: trifluoromethyl all-carbon quaternary centers, palladium catalysis, indoline, Heck reaction, trifluoromethyl