Regioselective Hydroarylation of Internal and Terminal Alkenes with Pyrazoles Enabled by a Lanthanum Catalyst

Catalytic C–H alkylation of pyrazoles with internal alkenes represents an ideal strategy for constructing functionalized pyrazoles—privileged heterocyclic scaffolds prevalent in pharmaceuticals, agrochemicals, and biologically active molecules. However, such a transformation has remained underexplored to date, likely due to the inherently low reactivity of internal alkenes and the lack of suitable catalysts. Herein, we describe a lanthanum-catalyzed highly regioselective C–H alkylation of N-arylpyrazoles with internal alkenes. The key to success of this unprecedented transformation is the use of an imidazolin-2-iminato lanthanum catalyst, whose large ionic radius provides an open coordination environment that facilitates the coordination of sterically demanding internal alkenes to the metal center and subsequent alkene migratory insertion. Beside internal alkenes, 1,1-disubstituted styrenes and terminal alkenes were amenable to the reaction. This protocol offers a straightforward and atom-efficient route for the synthesis of a new family of N-(ortho-alkylaryl)pyrazole derivatives (91 examples, up to 99% yield, >19:1 rr). The scale-up synthesis and further transformation to hedgehog enzyme inhibitor analog highlights the potential application of this method. On the basis of experimental and computational studies, the influence of metal ion size on the turn-over limiting migratory insertion step and the possible reaction mechanism were elucidated.