Efficient Synthesis of Aryl Fluorides
Efficient Synthesis of Aryl Fluorides
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DOI：
10.1002/anie.200905855
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Beller, Matthias
中科院分区：
文献类型：
--
作者：
Anbarasan, Pazhamalai;Neumann, Helfried;Beller, Matthias
芳香族和杂芳香族卤化物与碳、氧和氮亲核试剂的选择性官能化反应在过去的几十年里引起了人们的广泛关注。[1]除了典型的金属催化偶联反应，芳基卤化物通过形成格氏试剂的直接官能化为有效构建生物学上有趣的碳环和杂环提供了新的途径。[2，3]最近的优秀例子包括Knochel及其同事开发的LiCl介导的Grignard试剂制备。[4]受他们的工作和我们对芳基卤化物的官能化反应的兴趣的启发，[5]我们一直着迷于从芳基格氏试剂直接合成芳基氟化合物。尽管大量已知的药物和农用化学产品含有氟化芳烃（方案1），与非氟化类似物相比，其提高了溶解性，生物利用度和代谢稳定性，[6]，[7]它们的合成没有方便和通用的合成方法。将氟原子引入芳烃的公知方法需要相对苛刻的反应条件。典型的例子包括芳烃的直接缩合反应，[8]芳基重氮盐与HBF 4的Balz-Schiemann反应，[9]以及活化芳基卤化物与金属氟化物的Halex交换反应。[10]此外，过渡金属促进的氟化已经通过使用亲电性NH 4F试剂如Selectfluor或N-氟吡啶鎓盐实现。[11]不幸的是，在大多数这些反应中，必须使用化学计量的过渡金属，或者需要在底物上具有特定的导向基团。[12]最近，Buchwald和同事开发了一种使用AgF或CsF的芳基三氟甲磺酸酯的优雅的钯催化的双加成反应。[13我们的初步研究旨在使4-溴苯甲醚（1）（其是亲核取代的特别具有挑战性的底物）的取代以得到4-氟苯甲醚（2;表1）。
Selective functionalization reactions of aromatic and heteroaromatic halides with carbon, oxygen, and nitrogen nucleophiles have attracted much attention in the last decades.[1] In addition to typical metal-catalyzed coupling reactions, direct functionalization of aryl halides through the formation of Grignard reagents offer new ways for the efficient construction of biologically interesting carbo-and heterocycles.[2, 3] Recent elegant examples include the development of LiClmediated preparation of Grignard reagents by Knochel and co-workers.[4] Inspired by their work and our interest in functionalization reactions of aryl halides,[5] we have been fascinated in the direct synthesis of aryl fluoride compounds from aryl Grignard reagents.Although a large number of known pharmaceutical and agrochemical products contain fluorinated arenes (Scheme1), which enhance solubility, bioavailability, and metabolic stability compared with non-fluorinated analogues,[6, 7] there is no convenient and general synthetic method available for their synthesis. Commonly known methods for the introduction of a fluorine atom to arenes require relatively harsh reaction conditions. Typical examples include the direct fluorination of arenes,[8] the Balz–Schiemann reaction of aryldiazonium salts with HBF4,[9] and the so-called Halex exchange reaction of activated aryl halides with metal fluorides.[10] In addition, transition-metal-promoted fluorinations have been achieved through the use of electrophilic NÀF reagents such as Selectfluor or N-fluoropyridinium salts.[11] Unfortunately, in most of these reactions stoichiometric amounts of the transition metal must be used or specific directing groups on the substrate are required.[12] Most recently, Buchwald and co-workers developed an elegant palladium-catalyzed fluorination of aryl triflates using AgF or CsF.[13, 14] Our initial investigations aimed at the fluorination of 4-bromoanisole (1), which is a particularly challenging substrate for nucleophilic fluorination, to give 4-fluoroanisole (2; Table 1).