化学学报 ›› 2018, Vol. 76 ›› Issue (12): 977-982.DOI: 10.6023/A18080314 上一篇    下一篇

所属专题: 有机氟化学

研究通讯

铁催化下二芳基锌和芳基格氏试剂的二氟烷基化反应

安伦, 童非非, 张新刚   

  1. 中国科学院上海有机化学研究所 分子合成卓越中心 中国科学院有机氟化学重点实验室 上海 200032
  • 收稿日期:2018-09-18 出版日期:2018-12-15 发布日期:2018-12-11
  • 通讯作者: 张新刚,E-mail:xgzhang@sioc.ac.cn,Tel.:021-54925333,Fax:021-64166128 E-mail:xgzhang@sioc.ac.cn
  • 基金资助:

    项目受国家重点基础研究发展计划(973计划)(No.2015CB931900)、国家自然科学基金(Nos.21425208,21672238,21332010,21421002)和中国科学院先导专项(No.XDB20000000)资助.

Iron-Catalyzed Cross-Coupling of Diarylzinc or Aryl Grignard Reagents with Difluoroalkyl Bromides

An Lun, Tong Feifei, Zhang Xingang   

  1. Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
  • Received:2018-09-18 Online:2018-12-15 Published:2018-12-11
  • Contact: 10.6023/A18080314 E-mail:xgzhang@sioc.ac.cn
  • Supported by:

    Project supported by the National Basic Research Program of China (973 Program) (No. 2015CB931900), the National Natural Science Foundation of China (Nos. 21425208, 21672238, 21332010 and 21421002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB20000000).

随着医药、农药、材料等领域对含氟化合物日益增长的需求,发展向有机分子中直接引入氟原子和含氟基团的方法受到了化学家们的广泛重视.近些年来,过渡金属催化的氟烷基化反应,作为一种温和可控向有机分子引入含氟基团的策略得到了快速发展.与此同时,从反应的高效简洁和绿色温和性角度出发,发展廉价金属作为催化剂以及使用廉价易得的氟卤烷烃作为氟烷基试剂是非常具有吸引力的.本文以绿色低毒的Fe(acac)3为催化剂,首次实现了铁催化下二芳基锌与αα-二氟炔丙基溴的交叉偶联反应.该反应条件温和、原料廉价易得,产物可以放大到克量级制备,并能进行多种转化.此外,这一铁催化体系还可以实现芳基格氏试剂与二氟烷基溴代的偶联反应,为合成二氟烷基芳烃化合物提供了一种有效方法.初步的机理研究表明,该反应可能经历了单电子转移的自由基反应历程,偕二氟炔丙基自由基存在反应催化循环中.

关键词: 铁, 二芳基锌试剂, α,α-二氟炔丙基溴, 交叉偶联反应

The demanding of discovering new pharmaceuticals, agrochemicals and advanced functional materials have triggered extensive efforts on efficient synthesis of fluorinated compounds. Over the past decade, the transition-metal-catalyzed fluoroalkylation has emerged as an efficient and straightforward strategy for the synthesis of organofluorine compounds. Despite the importance of the reported synthetic methods, the development of environmentally benign and cost-efficient fluoroalkylation reactions with base metals as catalysis and widely available fluoroalkyl halides as fluoroalkyl sources continues to attract great interest. Here, we reported the first example of iron-catalyzed cross-coupling of diarylzinc reagents with gem-difluoropropargyl bromides. The reaction proceeds under mild reaction conditions and provides a facile access to gem-difluoropropargyl arenes. Additionally, this iron-catalytic system can also be applied to the cross-coupling of aryl Grignard reagents with difluoroalkyl bromides. Applications of the method led to modified bioactive molecules efficiently, offering potential opportunities in medicinal chemistry. Preliminary mechanistic studies reveal that a single electron transfer pathway is involved in the reaction. A representative procedure for iron-catalyzed cross-coupling of diarylzincs with gem-difluoropropargyl bromide is as following: Fe(acac)3 (10 mol%) was added to a 25 mL of Schlenck tube, the tube was then evacuated and backfilled with Ar (3 times). gem-Difluoropropargyl bromide 2 (0.3 mmol, 1.0 equiv.), TMEDA (0.45 mmol, 1.5 equiv.) and THF (1 mL) were then added, the reaction mixture was stirred at room temperature for 10 min and cooled to -20 ℃. A solution of diarylzinc reagent (0.45 mmol in 1.5 mL of THF, 1.5 equiv.) was added dropwise. After stirring for 4 h at -20 ℃, the reaction mixture was quenched with saturated NH4Cl solution. The yield was determined by 19F NMR before working up. If necessary, the reaction mixture was diluted with EtOAc and filtered with a pad of cellite. The filtrate was concentrated, and the residue was purified with silica gel chromatography to give product 3.

Key words: iron, diarylzinc reagents, gem-difluoropropargyl bromide, cross-coupling