Palladium-Catalyzed Direct C7-Arylation of Substituted Indazoles

Abstract

A novel direct C7-arylation of indazoles with iodoaryls is described using Pd(OAc)2 as catalyst, 1,10-phenanthroline as ligand, and K2CO3 as base in refluxing DMA. Direct C7-arylation of 3-substituted 1H-indazole containing an EWG on the arene ring gave the expected products in good isolated yields. In addition, a one-pot Suzuki-Miyaura/arylation procedure leading to C3,C7-diarylated indazoles has been developed.

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

“…in refluxing DMA for 24 h led to the desired C7-arylated products in yields ranging between 43 and 69% (only a few examples are selected here in Scheme 32). When the C3 position of 1H-indazole was not substituted, the arylation reaction of starting material 128 gave two different products: C3-arylated and C3/C7-diarylated products 129 and 125 in 61 and 21% yields, respectively (Scheme 32) [96]. Scheme 32.…”

Direct Catalytic Functionalization of Indazole Derivatives

“…[85] Guillaumet and co-workers first reported the direct regioselective method for C-7 arylation of substituted 1H-indazoles (23 a) by reacting with iodoaryl as coupling partner, Pd(OAc) 2 as a catalyst, 1,10-phenanthroline as a ligand and K 2 CO 3 as a base, K 3 PO 4 as an additive in refluxing DMA to obtain C-7 arylated 1Hindazole derivatives 23 b (Scheme 23). [86] The authors showed that 5-nitro-and 6-nitroindazoles produced mixtures of C-3 arylated and C-3/C-7 diarylated products but 4-nitroindazole gave only C-7 arylated product due to steric hindrance between the nitro group at the C-4 position and incoming group at the C-3 position. Explicitly, 7-nitroindazole produced only C-3 arylated product (Scheme 24).…”

“…Explicitly, 7-nitroindazole produced only C-3 arylated product (Scheme 24). [86] Furthermore, the group was able to demonstrate that the presence of electron-withdrawing groups on positions 4, 5 and 6 of indazole generated higher yields of C-7 arylated OMe] 2 /dptby catalytic system and Suzuki-Miyaura coupling with aromatic halides were occurred in presence of Pd(dppf)Cl 2 as a catalyst and Cs 2 CO 3 as a base in DMF at 100°C for 2 h (Scheme 25). [87] Under standard condition though aryl chloride was not viable as a coupling partner but a wide range of aryl and heteroaryl bromides and iodides were very effective.…”

1-Methyl-5-nitro-3-phenyl-1H-indazole

“…3-Substituted indazoles obtained from different cross-coupling reactions are common components of drugs and have been found to be of pharmaceutical interest in a variety of therapeutic areas (Cerecetto et al, 2005;Jennings et al, 2007;Sun et al, 1997, Bouissane et al, 2006Naas et al, 2014). They frequently comprise the core frame of numerous pharmaceutically active compounds, such as Lonidamine [1-(2,4-dichlorobenzyl)-1Hindazole-3-carboxylic acid] and Granisetron {1-methyl-N-[(1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]-1H-indazole-3-carboxamide}.…”