Preparation of p-substituted tetrafluoropyridyl derivatives via the tetrafluoropyridylcopper reagent

A new and improved preparation of 4-iodo-2,3,5,6-tetrafluoropyridine from pentafluoropyridine is described. This iodopyridine is utilized for the in situ preparation of the 4-tetrafluoropyridylcopper reagent, 1, via two methods. The first method involves metathesis of the 4-tetrafluoropyridylcadmium reagent with Cu(I)Br at room temperature. The requisite cadmium reagent was readily prepared in situ via reaction between 4-iodotetrafluoropyridine with acid-washed cadmium powder in DMF at room temperature. The second method involves the in situ reaction of 4-tetrafluoropyridyltributyl-phosphonium tetrafluoroborate with Na2CO3 and Cu(I)Br in DMF at room temperature. 1 readily undergoes reaction with allylic halides, vinyl iodides, aryl halides, acid chlorides and acetylenic iodides at room temperature to stereospecifically afford the corresponding 4-tetrafluoropyridyl derivatives. An alternative route to the alkyne derivatives was developed via the Pd(0) catalyzed reaction of 4-iodotetrafluoropyridine with 1-alkynes.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Improved preparation of 4-iodo-2,3,5,6-tetrafluoropyridine. ► In situ preparation of the 4-tetrafluoropyridylcopper reagent. ► Stereospecific preparation of 4-tetrafluoropyrdyl functionalized derivatives. ► New route to 4-alkynyltetrafluoropyridines.