钯催化的苯甲酸邻位碳氢键氟化反应研究

Palladium-Catalyzed ortho-C(sp^(2))-H Fluorination of Benzoic Acid

含氟有机分子通常具有一些独特的物理、化学以及生物学性质,因而在材料科学和药物化学中有着重要的应用价值。利用惰性碳氢键的活化来实现有机分子的官能团化近年来受到了极其广泛的关注,因此通过碳氢键的氟化反应来合成含氟有机分子也是有机合成中重要且具有挑战性的研究方向。以苯甲酸作为反应底物、以羧基作为导向基,通过对反应的添加剂、溶剂、氟化试剂和配体等进行筛选,实现了苯甲酸邻位碳氢键的氟化反应,以最高13%的分离收率得到了相应的单氟化产物。

Organic molecules with fluorine usually possess unique physical, chemical, and biological properties,thus playing an important role in material science and pharmaceutical chemistry. Meanwhile, the functionalization of organic molecules via C-H activation has drawn a broad attention in recent years. Therefore, C-H fluorination for the synthesis of fluorine-containing molecules is a very important and challenging project in organic synthesis. Directing groups such as pyridine and amide have been utilized to facilitate C-H fluorinations. However, most of the directing groups are usually installed into the substrates before the fluorination and uninstalled after the fluorination, thus reducing the step economy of the reaction. Carboxylic group is ubiquitous in organic molecules and it can dramatically increase the step economy if it is employed as native directing group. Indeed, it has been utilized as directing group in C-H activations such as arylation, olefination, acetoxylation. Carboxylic group directed C-H fluorination remains a challenge. In this research, by using the carboxylic group as a directing group, after optimization of the reaction conditions including additive, solvent, fluorination reagent and ligand, we realized the Pd-catalyzed ortho-C(sp^(2))-H fluorination of benzoic acid, which affords the ortho-mono-fluorinated product in up to 13% isolated yield. A pyridone ligand with a nitro group at the C-5 position and an amide group at the C-3 position was found to be able to promote this transformation. We believe that these results will benefit future development of carboxylic group directed C-H fluorination.