Pyrazole is an important heterocycle that is frequently found in drugs and ligands for transition metals. Generally, electrophilic aromatic substitution favors the C4 position of pyrazole, whereas strong-base-mediated substitution occurs at the C5 position of pyrazole. However, the transition-metal-catalyzed C−H functionalization has not yet been able to take advantage of the electronic difference between the (C4/C5)−H bonds and mixtures of mono- and disubstituted products have been obtained. In this work, we achieved regioselective C4-, C5- and dialkenylation of pyrazoles by three distinctive Pd-catalyzed systems. An electrophilic Pd catalyst generated by trifluoroacetic acid (TFA) and 4,5-diazafluoren-9-one (DAF) led to C4-alkenylation, whereas KOAc and monoprotected amino acid (MPAA) ligand Ac-Val-OH enabled C5-selective alkenylation. A combination of palladium(II) acetate, silver carbonate, and pivalic acid afforded the corresponding dialkenylation products. Kinetic isotope effects and H/D exchange experiments were performed in order to obtain mechanistic insights into C4- and C5-alkenylation. These Pd-catalyzed protocols gave a wide range of alkenylated products from readily available, low-cost pyrazoles and alkenes. In addition, an annulative approach involving sequential alkenylation of pyrazoles, thermal 6p-electrocyclization and oxidation provided functionalized indazoles. This comprehensive strategy greatly expanded the range of readily accessible pyrazole and indazole derivatives and will be useful in the development of regiodivergent C−H functionalization of pyrazoles and other heteroaromatic systems.

Ligand-controlled regiodivergent C−H alkenylation of pyrazoles

256th National Meeting (2018)

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