Direct Acyl Radical Addition to 2H-Indazoles Using Ag-Catalyzed Decarboxylative Cross-Coupling of α-Keto Acids

Abstract

A direct acyl radical addition to 2 H-indazoles has been achieved for the first time, where the less-aromatic quinonoid 2 H-indazoles readily accepted radical species to the C-3 position. Motivated by the lack of direct acylation strategy for 2 H-indazoles, the current method utilizes the radical acceptability of 2 H-indazoles, discovering an ambient temperature reaction to provide facile access to a diverse array of 3-acyl-2 H-indazoles with three points of structural diversification in 25%-83% yields.

Continuous‐Flow Visible Light Organophotocatalysis for Direct Arylation of 2H‐Indazoles: Fast Access to Drug Molecules

“…Fluorine‐ and bromine‐substituted 2 H ‐indazole at C6 provided the desired product 3 e and 3 f with good yields in the range of 60–68 % in both batch and flow processes, and the C7‐methoxy‐substituted 2 H ‐indazole also gave very good yields ( 3 g ; 65 % batch, 72 % flow). N2 substituents of 2 H ‐indazoles with heteroaryl, alkyl, and benzyl, unfortunately failed to form the desired products (Table , 3 h – j ), presumably owing to the less aromatic character of 2 H ‐indazole …”

“…[14] Commercially important drugss uch as MK-4827 (anticancer activity) [15] and pazopanib (tyrosinek inase inhibitor,v otrient) [16,17] incorporate indazole as ab asic scaffold.Functionalization of 2H-indazolesl eads to formation of privileged structural motifs that can be transformed into diverse scaffoldsi na grochemicals and pharmaceuticals. Despitei ts importance, not many reports are available [18][19][20][21] relative to the numerous reports on substituted 1H-indazoles, [22][23][24][25][26] presumably because of the low reactivity at C3 position of 2H-indazoles [27][28][29] arising from their less aromatic character of quinonoid form [27][28][29] that obstructs formation of functionalized or fused derivatives.Of the functionalized 2H-indazoles, non-arylated scaffolds have been synthesized by C3 alkenylation, [30] annulation, [31] acylation, [27] phosphonylation, [32] nitration, [33] andt rifluoromethylation. [34] However,f ar fewer attempts have been made for the direct arylation of 2H-indazolesa tt he C3 position, including a few reports of Negishic ross-coupling [35] and arylation by aryl halides, [36][37][38][39] which required Cu or Pd metal catalysts, expensive ligands, andmany additives (base, oxidant) with long reaction times (Scheme 1).…”

“…Functionalization of 2H-indazolesl eads to formation of privileged structural motifs that can be transformed into diverse scaffoldsi na grochemicals and pharmaceuticals. Despitei ts importance, not many reports are available [18][19][20][21] relative to the numerous reports on substituted 1H-indazoles, [22][23][24][25][26] presumably because of the low reactivity at C3 position of 2H-indazoles [27][28][29] arising from their less aromatic character of quinonoid form [27][28][29] that obstructs formation of functionalized or fused derivatives.…”

“…Of the functionalized 2H-indazoles, non-arylated scaffolds have been synthesized by C3 alkenylation, [30] annulation, [31] acylation, [27] phosphonylation, [32] nitration, [33] andt rifluoromethylation. [34] However,f ar fewer attempts have been made for the direct arylation of 2H-indazolesa tt he C3 position, including a few reports of Negishic ross-coupling [35] and arylation by aryl halides, [36][37][38][39] which required Cu or Pd metal catalysts, expensive ligands, andmany additives (base, oxidant) with long reaction times (Scheme 1).…”

“…N2 substituents of 2H-indazoles with heteroaryl, alkyl, and benzyl, unfortunately failed to form the desired products (Table 3, 3h-j), presumably owing to the less aromatic character of 2H-indazole. [27][28][29] With respectt oa ryldiazonium salts, the potentialo ft he present methodology was examined for various salts with ortho, meta,a nd para,a sw ell as multiple substituents.T he desired arylated products were obtained in good to very good yields (up to 85 %) in the presence of both electron-donating Scheme1.Comparison of approaches for directC3a rylationo f2 H-indazoles between previousr eports and this work. ( Table 4, 3k-n)a nd electron-withdrawing (Table 4, 3o-u)s ubstituents.…”