全氟烷基卤化物作为含氟砌块在构建氟烷基取代杂环化合物中的研究进展

doi:10.6023/cjoc202009035

摘要/Abstract

有机氟化学和杂环化学的研究对药物研发、新材料制备等方面具有重要意义. 过去几年中, 利用高度商业化、低毒性、廉价、稳定、易操作的全氟烷基卤化物为含氟砌块构建氟烷基取代杂环化合物取得了重要进展. 本综述将全氟烷基卤化物作为含氟砌块参与构建杂环化合物的报道进行总结: (1)通过全氟烷基卤化物的单个碳卤键官能化构建杂环化合物; (2)通过全氟烷基卤化物的多个碳卤键官能化构建杂环化合物. 通过全氟烷基卤化物产生全氟烷基自由基(?R_f)继而对不饱和类型底物进行加成-环化串联, 将含氟基团引入杂环, 合成了一系列氟烷基取代杂环化合物, 如喹氧啉、菲蒽、肼、噻唑、嘧啶、偶氮三环、异噁唑等. 本文旨在为从事有机杂环合成和有机氟化学的研究人员提供参考和启示, 从而有助于新的含氟砌块和新的氟化反应的设计开发.

关键词: 全氟烷基卤化物, 含氟砌块, 氟烷基取代杂环, 环化反应, 自由基反应

The unique chemical and physical advantages conferred by incorporation of F-atoms/perfluoroalkyl groups (R_f) into organic compounds have gained widespread recognition throughout drug discovery, crop protection, polymer chemistry, and materials science. The past decades have witnessed a boom in organofluorine chemistry and heterocyclic chemistry mainly owing to the importance of fluorine-containing heterocycles. As a result, the exploitation of readily available fluorinated building blocks to attach R_f groups to various heterocycles has become an important topic in synthetic chemistry. On the other hand, perfluoroalkyl halide, as a low-toxic and environmentally friendly perfluoroalkyl building block, has been extensively utilized as a unique reagent in the heterocycle construction. Considering the great influence and synthetic potential of these novel avenues, we summarize the recent advances for the synthesis of fluoroalkylated heterocycles by using perfluoroalkyl halides as key fluorine-containing building blocks. One or three C—X bonds of perfluoroalkyl halides are cleaved/functiona- lized during the perfluoroalkylation and cyclization process, and a series of perfluoroalkylated heterocycles such as quinoxalines, phenanthridines, hydrazones, thiazoles, pyrimidines, aza-tricycles, isoxazoles,etc. were synthesized in moderate to good yields. With a specific emphasis on their proposed mechanism, we hope this review will be useful for medicinal and synthetic organic chemists who are interested in radical-mediated perfluoroalkylation.

Key words: perfluoroalkyl halide, fluorine-containing building block, fluoroalkylated heterocycle, cyclization, radical reaction

引用此文

程步清, 葛丹华, 汪欣, 褚雪强. 全氟烷基卤化物作为含氟砌块在构建氟烷基取代杂环化合物中的研究进展[J]. 有机化学, 2021, 41(5): 1925-1938.

Buqing Cheng, Danhua Ge, Xin Wang, Xueqiang Chu. Perfluoroalkyl Halides as Fluorine-Containing Building Blocks for the Synthesis of Fluoroalkylated Heterocycles[J]. Chinese Journal of Organic Chemistry, 2021, 41(5): 1925-1938.

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图/表 20

图1. 代表性多氟烷基取代生物活性、药物活性分子

Figure 1. Representative biologically active perfluoroalkylated molecules and drugs

图2. 多氟烷基卤化物作为含氟砌块构建杂环化合物

Figure 2. Perfluoroalkyl halides as fluorine-containing building blocks for the synthesis of heterocycles

图式1. 可见光照射下的卤素键促进的双自由基异腈插入合成2-氟烷基化喹喔啉

Scheme 1. Halogen-bond-promoted double radical isocyanide insertion under visible-light irradiation: synthesis of 2?fluoro- alkylated quinoxalines

图式2. 光催化条件下的全氟烷基化反应

Scheme 2. Halogen-bond-promoted perfluoroalkylation reactions via photoactivation of perfluoroalkyl iodides

图式3. 可见光促进的β,γ-不饱和腙化合物的全氟烷基化环化反应

Scheme 3. Ambient-light-promoted perfluoroalkylative cyclization of β,γ-unsaturated hydrazones

图式4. 钯催化未活化烯烃的芳基全氟烷基化反应合成杂环化合物

Scheme 4. Pd-catalyzed arylperfluoroalkylation of unactivated olefins for the synthesis of heterocycles

图式5. 铜/铁协同催化的1,6-烯炔的氟代烷基化环化反应

Scheme 5. Copper/iron-co-catalyzed cascade perfluoroalkylation/cyclization of 1,6-enynes with iodoperfluoroalkanes

图式6. EDA配合物的可见光诱导自由基全氟烷基化/环化反应

Scheme 6. Visible-light induced radical perfluoroalkylation/cyclization strategy by EDA complex

图式7. 可见光诱导的全氟烷基卤化物与1,n-炔烃的环化反应

Scheme 7. Visible-light-induced cyclization of perfluoroalkyl halides with 1,n?enynes

图式8. 铜催化苯甲酰亚胺高烯丙酯的分子内胺化全氟烷基化反应

Scheme 8. Copper-catalyzed intramolecular aminoperfluoroalkylation reaction of O?homoallyl benzimidates

图式9. 铜促进的未活化烯烃的芳基全氟烷基化

Scheme 9. Cu-mediated arylperfluoroalkylation of unactivated alkenes

图式10. 铁催化的烯烃和炔烃的碳氮双官能化反应

Scheme 10. Iron-catalyzed carboazidation of alkenes and alkynes

图3. 多氟烷基卤化物的C—X键断裂

Figure 3. Activation of C—X bonds in perfluoroalkyl halides

图式11. 环境光促进的三组分环化反应合成全氟烷基化嘧啶化合物

Scheme 11. Ambient-light-promoted three-component annulation for the synthesis of perfluoroalkylated pyrimidines

图式12. 环境光促进的含全氟烷基的氮杂三环的合成

Scheme 12. Ambient-light-promoted cyclization for the synthesis of perfluoroalkyl-containing aza-tricycles

图式13. 铜催化的苄脒盐酸盐、苯乙烯和全氟代烷基卤的三组分环化反应

Scheme 13. Copper-catalyzed three-component cyclization of amidines, styrenes, and fluoroalkyl halides

图式14. 可见光促进氟烷基化和脱氟实现[3+2+1]杂环化反应

Scheme 14. Visible-light promoted fluoroalkylation and defluorination to enable formal [3+2+1] heteroannulation

图式15. 可见光氧化还原催化的化学和区域选择性杂环构建

Scheme 15. Chemo- and regio-selective ring construction by visible light photoredox catalysis

图式16. EDA配合物引发的可见光促进的[5+1]环化合成全氟烷基-s-三嗪

Scheme 16. Visible-light-promoted [5+1] annulation for the synthesis of perfluoroalkyl?s?triazines

图式17. 合成全氟烷基异噁唑的四组分环化反应

Scheme 17. Four-component cyclization for the synthesis of perfluoroalkyl isoxazoles

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