Mechanochemical Synthesis of PdO 2 Nanoparticles Immobilized over Silica Gel for Catalytic Suzuki-Miyaura Cross-Coupling Reactions Leading to the C-3 Modification of 1 H -Indazole with Phenylboronic Acids.

The C-3 modification of 1 H -indazole has produced active pharmaceuticals for the treatment of cancer and HIV. But, so far, this transformation has seemed less available, due to the lack of efficient C-C bond formation at the less reactive C-3 position. In this work, a series of silica gel-supported PdO 2 nanoparticles of 25-66 nm size were prepared by ball milling silica gel with divalent palladium precursors, and then employed as catalysts for the Suzuki-Miyaura cross-coupling of 1 H -indazole derivative with phenylboronic acid. All the synthesized catalysts showed much higher cross-coupling yields than their palladium precursors, and could also be reused three times without losing high activity and selectivity in a toluene/water/ethanol mixed solvent. Although the palladium precursors showed an order of activity of PdCl 2 (dppf, 1,1'-bis(diphenylphosphino)ferrocene) > PdCl 2 (dtbpf, 1,1'-bis(di- tert -butylphosphino)ferrocene) > Pd(OAc, acetate) 2 , the synthesized catalysts showed an order of C1 (from Pd(OAc) 2 ) > C3 (from PdCl 2 (dtbpf)) > C2 (from PdCl 2 (dppf)), which conformed to the orders of BET (Brunauer-Emmett-Teller) surface areas and acidities of these catalysts. Notably, the most inexpensive Pd(OAc) 2 can be used as a palladium precursor for the synthesis of the best catalyst through simple ball milling. This work provides a highly active and inexpensive series of catalysts for C-3 modification of 1 H -indazole, which are significant for the large-scale production of 1 H -indazole-based pharmaceuticals.