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Acta Chim. Sinica ›› 2016, Vol. 74 ›› Issue (1): 61-66.DOI: 10.6023/A15090587 Previous Articles     Next Articles

Article

碳正离子Lewis酸催化氧化还原中性胺基α-C(sp3)H芳基化反应

张启超, 吕健, 罗三中   

  1. 中国科学院化学研究所 北京分子科学国家实验室 分子识别与功能院重点实验室 北京 100190
  • 投稿日期:2015-09-06 发布日期:2015-10-29
  • 通讯作者: 吕健, 罗三中 E-mail:lvjian@iccas.ac.cn;luosz@iccas.ac.cn
  • 基金资助:

    项目受国家自然科学基金(Nos. 21390400, 21202170, and 21472193)和973项目(No. 2012CB821600).

Carbocation Lewis Acid Catalyzed Redox-Neutral α-C(sp3)H Arylation of Amines

Zhang Qichao, Lü Jian, Luo Sanzhong   

  1. Beijing National Laboratory for Molecular Sciences BNLMS, CAS Key Laboratory of Molecular Recognition and Functions, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190
  • Received:2015-09-06 Published:2015-10-29
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 21390400, 21202170, 21472193) and 973 program (No. 2012CB821600).

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Supporting Info.

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The α-substituted nitrogen-containing heterocycles (N-heterocycles) like tetrahydroisoquinolines (THIQs) and piperidines are common in nature and are present as the key functional group in bioactive and pharmacologically active compounds. The two traditional approaches for the synthesis of α-substituted N-heterocycles are Pictet-Spengler condensation and hydrogenation of the α-substituted cyclic imines. Recently, direct C(sp3)-H functionalization of N-heterocycles with various nucleophiles catalyzed by transition metal complex under the oxidants presents an atom-economic protocol without prior installation of activating group. However, new catalytic strategy or catalysts are still desirable in order to further address the use of excess oxidants and expensive transition metal complex. Stable carbocations, such as tritylium ions, have been widely used as organic Lewis acid catalysts and reagents in organic synthesis. In our studies, it was found that tritylium salts [Ph3C][BArF] (10 mol%) in situ generated by Ph3CBr (0.02 mmol) and NaBArF (0.02 mmol) could promote the three component redox-neutral α-arylation of amines reaction with tetrahydroisoquinoline 2 (0.3 mmol), aldehyde 3 (0.2 mmol) and indole 4 (0.3 mmol) in toluene (1.0 mL) to afford the desired α-substituted N-heterocyclic compounds 5 in good yields (up to 99% yield) at ambient temperature to 50 ℃. To our satisfaction, a variety of differently substituted indoles 4a～4i could work well with tetrahydroisoquinoline 2 and 2,6-dichlorobenzaldehyde 3a to provide the corresponding α-substituted N-heterocyclic compounds 5a～5i in good to excellent yields at room temperature. When other substituted benzaldehydes 3b～3f were used, the reactions could also proceed smoothly to give the compounds 5j～5o with moderate yield (up to 66% yield) at 50 ℃. Moreover, we have also developed redox-neutral α-arylation of tetrahydroisoquinoline 2 with other aromatic nucleophile such as substituted phenol, b-naphthol and pyrrole under the optimal reaction conditions. Importantly, the model reaction, conducted in the presence of Na2CO3(1.0 equiv.) or 2,6-bis(tert-butyl) pyridine (0.5 equiv.) at room temperature in toluene also proceeded smoothly to give the desired adduct 5a with comparable yields (82% and 92% yield, respectively), which could exclude the possibility of free acid catalysis in this reaction.

Key words: carbocation, Lewis acid, redox-neutral reaction, α-C(sp3)H arylation, organocatalysis