Motati Damoder Reddy, Uredi Dilipkumar, Watkins E Blake
Department of Pharmaceutical Sciences , College of Pharmacy , Union University , Jackson , Tennessee , 38305 USA . Email:
Chem Sci. 2018 Jan 5;9(7):1782-1788. doi: 10.1039/c7sc04107a. eCollection 2018 Feb 21.
An operationally simple and metal-free protocol for geometrically inaccessible C5-H halogenation of a range of 8-substituted quinoline derivatives has been established. The reaction proceeds under air, with inexpensive and atom economical trihaloisocyanuric acid as a halogen source (only 0.36 equiv.), at room temperature. Exceptionally high generality with respect to quinoline is observed, and in most instances, the reaction proceeded with complete regioselectivity. Quinoline with a variety of substituents at the 8-position gave, exclusively, the C5-halogenated product in good to excellent yields. Phosphoramidates, tertiary amides, -alkyl/,-dialkyl, and urea derivatives of quinolin-8-amine as well as alkoxy quinolines were halogenated at the C5-position remote functionalization for the first time. This methodology provides a highly economical route to halogenated quinolines with excellent functional group tolerance, thus providing a good complement to existing remote functionalization methods of quinolin-8-amide derivatives and broadening the field of remote functionalization. The utility of the method is further showcased through the synthesis of several compounds of biological and pharmaceutical interest.
已建立了一种操作简单且无金属的方法，用于一系列8-取代喹啉衍生物的几何上难以接近的C5-H卤化反应。该反应在空气中进行，以廉价且原子经济的三卤异氰尿酸作为卤源（仅0.36当量），在室温下进行。观察到喹啉具有极高的通用性，并且在大多数情况下，反应具有完全的区域选择性。在8位带有各种取代基的喹啉仅以良好至优异的产率得到C5-卤化产物。喹啉-8-胺的磷酰胺、叔酰胺、-烷基/、-二烷基和脲衍生物以及烷氧基喹啉首次在C5位进行了远程官能化。该方法提供了一条高度经济的路线来合成具有优异官能团耐受性的卤代喹啉，从而为喹啉-8-酰胺衍生物现有的远程官能化方法提供了良好的补充，并拓宽了远程官能化领域。通过合成几种具有生物学和药学意义的化合物，进一步展示了该方法的实用性。
