Site Selective Chlorination of C(sp3)​-​H Bonds Suitable for Late-​Stage Functionalization

Site Selective Chlorination of C(<i>sp</i><sup>3</sup>)​-​H Bonds Suitable for Late-​Stage Functionalization

Angew. Chem. Int. Ed.  202160,  8276-8283.

C(sp3)−Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp3)−H bond. However, most current methods for the chlorination of C(sp3)−H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late-stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp)−H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H-atom abstractor under mild conditions, and a readily-accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late-stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients. Read more on publisher's site.