Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Nat Chem. 2017 Sep;9(9):918-923. doi: 10.1038/nchem.2746. Epub 2017 Mar 14.
Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCFH), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CFH) from ClCFH into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCFH with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal-difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal-difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understand metal-difluorocarbene complex catalysed reactions.
二氟甲基化芳香族化合物在药物、农业化学品和材料领域的重要性日益增加。氯二氟甲烷（ClCFH）是一种廉价、丰富且广泛使用的工业原料，代表了理想且最直接的二氟甲基化试剂，但从未有报道将 ClCFH 中的二氟甲基（CFH）引入芳香族化合物中。在这里，我们描述了一种直接的钯催化二氟甲基化方法，用于将 ClCFH 与芳基硼酸和酯偶联，以高效地生成二氟甲基化芳烃。该反应具有非常广泛的底物范围，包括杂芳基硼酸，并被用于一系列药物和生物活性化合物的二氟甲基化。初步的机理研究表明，反应涉及钯二氟卡宾中间体。尽管已经制备了许多金属二氟卡宾配合物，但涉及金属二氟卡宾配合物的二氟甲基化或二氟亚甲基化化合物的催化合成并未受到太多关注。因此，这项新反应也为理解金属二氟卡宾配合物催化反应开辟了道路。
