Institute of Organic Chemistry, University of Vienna, Vienna, Austria.
Centre of Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Nat Chem. 2019 Apr;11(4):329-334. doi: 10.1038/s41557-019-0215-z. Epub 2019 Mar 4.
Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs. State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolonium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C-H-fluorination of amides. Reduction of these products enables facile access to β-fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, is presented as an example of the preserved biological activity after fluorination.
鉴于氟的独特性质，以及氟化能够改变有机分子的性质，药用化学家对能够合成新的氟化基序的创新方法产生了浓厚的兴趣。α-氟化羰基化合物的最先进合成方法通常依赖于亲电氟化剂，这些氟化剂可能具有很强的氧化性并且难以处理。在这里，我们表明通过将烯醇化物的极性反转到烯醇翁的极性，可以使用亲核氟化剂对酰胺进行直接选择性α-C-H-氟化。这些产物的还原可使β-氟化胺的制备变得容易，并且通过轻松制备许多药物和农用化学品的氟化类似物证明了该方法的价值。作为氟化后生物活性保留的示例，提供了一种市售抗抑郁药西酞普兰的氟化类似物。
