The C-3 Functionalization of 1H-Indazole through Suzuki–Miyaura Cross-Coupling Catalyzed by a Ferrocene-Based Divalent Palladium Complex Immobilized over Ionic Liquid, as Well as Theoretical Insights into the Reaction Mechanism

Abstract

The C-3 functionalization of 1H-indazole could produce a lot of highly valuable pharmaceutical precursors, which could be used for the treatment of cancer and many other inflammatory diseases. This work was focused on the C-3 functionalization of 1H-indazole through Suzuki–Miyaura cross-coupling of 3-iodo-1H-indazole with organoboronic acids, catalyzed by various palladium catalysts immobilized over imidazolium ionic liquids, as well as catalyst recycling. A series of reaction parameters, including the substrate, catalyst, and ionic liquid, were fully investigated. It is significant to note that the yields of the present Suzuki–Miyaura cross-coupling were mainly determined by the catalyst and the solvent used, more than the chemical structure of the substrate. Furthermore, ferrocene-based divalent palladium complexes showed better catalytic outputs compared to simple palladium salts. Moreover, using two imidazolium ionic liquids, BMImX (BMIm+ = 1-n-butyl-3-methylimidazolium, X− = BF4−, PF6−) not only improved the yields of cross-coupled products, but also avoided the formation of Pd(0) black, as compared to the non-ionic liquid facilitated reactions, and simultaneously making catalyst recycling more effective. On average, BMImBF4 performed better than BMImPF6. Additionally, scientific calculations revealed that 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (PdCl2(dppf)) showed a lower energy barrier in the formation of intermediates than [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dtbpf)), leading to higher catalytic outputs. This work may contribute to the development of 1H-indazole-derived new pharmaceuticals.

Mechanochemical Synthesis of PdO2 Nanoparticles Immobilized over Silica Gel for Catalytic Suzuki–Miyaura Cross-Coupling Reactions Leading to the C-3 Modification of 1H-Indazole with Phenylboronic Acids

“…From another point of view, the yield stemming from the protocol of Table 4 catalyzed by C2 (entry 12, Table 4; yield of 88%) was much higher than that from the same reaction catalyzed by PdCl 2 (dppf) (yield of 65%) [43]. Furthermore, C2 also showed a very close yield compared to the catalytic combination of PdCl 2 (dppf) with BMImPF 6 [45]. These results clearly indicate that the ball milling of the divalent palladium(II) precursor with silica gel produces a highly active palladium catalyst.…”

“…It has been widely reported that the immobilization of palladium species into ionic liquid can provide more powerful catalysts for Suzuki-Miyaura cross-coupling, mainly because this kind of immobilization can increase the acidity of the palladium component, stabilize the active intermediate, inhibit the formation of non-catalytic palladium black, as well as improve catalyst recycling [45,46]. However, the suitable palladium components may be limited to homogeneous palladium salts or complexes rather than supported palladium materials.…”

“…In comparison, the ligand of the palladium(II) precursor stabilized the intermediate during oxidative addition, but this effect became marginal on the surface of the PdO 2 nanoparticles, where surficial hydroxyl groups turned out to be great substitutes for those ligands. On the other hand, although the immobilization of homogeneous palladium(II) complexes into ILs enhanced both oxidative addition and transmetallation [45,46], the dispersion of PdO 2 nanoparticles immobilized over silica gel into ILs was not successful, probably because the surface of the PdO 2 nanoparticles was saturated and the internal pores were blocked by ILs.…”

Ullmann-Type N-, S-, and O-Arylation Using a Well-Defined 7-Azaindole-N-oxide (7-AINO)-Based Copper(II) Catalyst: Scope and Application to Drug Synthesis

“…3-Iodoindazole was prepared according to literature procedures . A solution of 1 H -indazole (1 g, 8.4646 mmol), iodine (2 equiv), and potassium hydroxide (3.75 equiv) in DMF (5 mL) was stirred for 3 h at room temperature.…”