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0 26070238 - 26070238

DOI: https://doi.org/10.6023/A26070238

Article

Palladium-Catalyzed Interrupted Heck Reaction for Direct Access to Allylic CF3-Substituted All-Carbon Quaternary Centers

  • Ma Pei-Yan ,
  • Wen Yongshun ,
  • Zhang Yi-Hai ,
  • Luo Wenjun ,
  • Long Lipeng ,
  • Chen Zhengwang ,
  • Tang Shaobin ,
  • Peng Xiangjun ,
  • Yu Daohong
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  • aJiangxi Province Key Laboratory of Synthetic Pharmaceutical Chemistry, College of Chemistry and Materials Science, Gannan Normal University, Ganzhou, 341000, China;
    bKey Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, School of Pharmaceutical Sciences of Gannan Medical University, Ganzhou, 341000, China

Received date: 2026-07-08

  Online published: 2026-09-07

Supported by

National Natural Science Foundation of China (22461002, 22261004), Natural Science Foundation of Jiangxi Province (20232BCJ25050, 20243BCE51174, 20242BAB20110, 20244BAB28057), the State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials (2026PT0005).

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Abstract

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

Cite this article

Ma Pei-Yan , Wen Yongshun , Zhang Yi-Hai , Luo Wenjun , Long Lipeng , Chen Zhengwang , Tang Shaobin , Peng Xiangjun , Yu Daohong . Palladium-Catalyzed Interrupted Heck Reaction for Direct Access to Allylic CF3-Substituted All-Carbon Quaternary Centers[J]. Acta Chimica Sinica, 0 : 26070238 -26070238 . DOI: 10.6023/A26070238

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