Palladium‐Catalyzed Regioselective C−H Arylation of 4‐Azaindazole at C3, C5 and C7 Positions

Abstract

Direct and site‐selective C5 and C7 palladium‐catalyzed C−H arylations of 4‐azaindazole N‐oxide have been achieved. A bidentate ligand and Pd(OAc)2 catalyst in toluene promoted the activation of C5 position, while a phosphine ligand and PdCl2 catalyst in DMA directed the arylation at C7 position. Using this new method, the synthesis of C5, C7‐diarylated 4‐azaindazole N‐oxides as well as the C3, C5, C7‐triarylated 4‐azaindazoles was achieved towards future medicinal compounds development.

Solvent/Ligand-Controlled Switchable C3 or C7 C–H Arylations of 1-Methyl-4-nitro-1H-indazole

“…Under the previous study conditions (vide supra), no reaction occurred using water instead of DMA (Table 2 , entry 1). Then, drawing on our previous work, 24 25 we tested various Pd(II) as catalysts in the presence of 3 equivalents of 4-iodobenzene, PPh 3 as ligand, Ag 2 CO 3 as the base in H 2 O as solvent at 140 °C for 48 hours in a sealed tube. With Pd(PPh 3 )Cl 2 or PdCl 2 , only starting material 2 was recovered in 88 % and 70% yield, respectively (entries 2 and 3).…”

“…Under the previous study conditions (vide supra), no reaction occurred using water instead of DMA (Table 2, entry 1). Then, drawing on our previous work, 24,25 we Scheme 2 Limitations of the C7 arylation reaction.…”

“…In our very recent report we showed that the use of N-oxide as directing group led to solvent/ligand controlled regioselective C5 and C7 arylation of 4-azaindazole N-oxides catalyzed by palladium without any need to block the C3 position. 24 In fact, the reaction catalyzed by PdCl2 in the presence of a combination of DMA/triphenylphosphine (PPh3) as solvent and ligand respectively, led to site-selective C7 arylation, while the use of Pd(OAc)2 as catalyst in the presence of 1,10-phenanthroline (phen) in toluene provided the selective C5 arylation.…”

“…In the case of the 4-nitro-1H-indazole, C7 arylation using a Pd(OAc) 2 /phen system was achieved without the blockage of the C3 position, but the reaction yield was low even when a large excess of iodotoluene was used. 25 In continuation of our research program toward the development of site-selective C-H activation of the six-membered rings of 6,5-fused heterocyclic systems, [24][25][26] we report herein a site-selective arylation of the 4-nitro-1H-indazole at either the C3 or the C7 position by means of new reaction conditions that allow perfect control of the regioselectivity. This control of the arylation reaction is mainly governed by the nitro group at the C4 position as well as the nature of the solvent assisted by the ligand.…”

Regioselective C-H Functionalization of the Six-Membered Ring of the 6,5-Fused Heterocyclic Systems: An Overview

“…Very recently, our group [ 97 ] has developed a highly regioselective direct arylation at C5 and C7 positions of the azine ring of pyrazolo[4,3-b]pyridines (4-azaindazole). The N- oxide group increases the electron density of the pyridine ring, thus favoring productive π-binding interaction with the arene ring.…”