Metal-free benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids

Abstract

A simple and straightforward approach has been realized for the direct regioselective benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids in the presence of K2S2O8 as oxidant. Various functional...

Oxidant-Switched Palladium-Catalyzed Regioselective Mono- versus Bis-ortho-Aroylation of 1-Aryl-1H-indazoles with Aldehydes via C–H Bond Activation

“…The optimization of direct regioselective C (sp 2 ) –H/C (sp 2 ) –H CDC of mono/bis- ortho -aroylation is commenced by taking 1-phenyl-1 H -indazole 1a and p -tolualdehyde 3a as the starting substrates (Table ). It has also been well documented in the literature that numerous aldehyde derivatives or other benzoyl/acyl surrogates generate benzoyl/acyl free radical after treatment with organic oxidants that had been applied in various oxidative cross-dehydrogenative coupling reactions. , Moreover, it has been anticipated that the metal-catalyzed oxidative coupling with a chelating site can result in the formation of the ortho -aroylation product. Initially, PdCl 2 as the catalyst and tert -butyl hydroperoxide (TBHP) as an oxidant were chosen for our optimization study.…”

“…To gain deep insight into and investigate the mechanistic details of the developed protocol, several diverse control experiments were conducted (Scheme , eqs i–viii). It has already been demonstrated in the literature that in the presence of organic oxidants, various aromatic/aliphatic aldehydes generate benzoyl or acyl free radicals, which then upon incorporation with a transition-metal-catalyzed chelation-assisted metallocycle afforded the ortho -substituted product regioselectively. , Therefore, on the basis of literature precedent, initially, the free radical scavenger experiment was carried out while the optimal reaction parameters remained unchanged, 1a was reacted with 3a in the presence of TEMPO (1 equiv), which resulted in the formation of 4a in 51% yield (Scheme , eq i). However, 4a vanished, and the reaction was completely terminated when TEMPO (2.5 equiv) was used under the standard reaction conditions (Scheme , eq ii).…”

“…General Procedure for the Synthesis of [2-(1H-Indazol-1yl)phenyl](p-tolyl)methanol (8). To a solution of 4a (0.5 mmol) in methanol (10−15 mL) was added portionwise NaBH 4 (2.0 mmol) at ambient temperature, and the reaction mixture was allowed to stir at the same temperature for ∼1 h. After the reaction had reached completion, the mixture was cooled to room temperature, the solvent was allowed to concentrate under reduced pressure, and the desired crude solid product was extracted with ethyl acetate (3 × 20 mL) and water (10 mL).…”

“…[2-(1H-Indazol-1-yl)phenyl](p-tolyl)methanol (8). Product 8 was obtained through the use of the general procedure and was separated using column chromatography (95:5 hexane/EtOAc) as a viscous solid in 90% yield (91 mg, 0.29 mmol): R f = 0.35 (85:15 hexane/ EtOAc); 1 H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68−7.62 (m, 4H), 7.57−7.52 (m, 2H), 7.43−7.39 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 5.17 (br, 1H), 2.40 (s, 3H); 13 C{ 1 H} NMR (100 MHz, chloroform-d) δ 141.…”

“…In this context, the direct, regioselective, sitecontrolled mono/bis-ortho-functionalization(s) of 1-phenyl-1H-indazole is an indisputably challenging area of investigation in the field of organic synthesis. Few research groups, including ours, 2a have made pioneering contributions 8 to the functionalization of the C−H bond through oxidant-promoted CDC reactions in which several substituted aromatic/heteroaromatic/aliphatic aldehydes, upon treatment with organic oxidants in the presence of a metal catalyst or under metal-free conditions, generate benzoyl/acyl surrogates that are attached to the active position/chelationassisted activated position via C−H bond activation to furnish the desired C−H functionalization. However, the development of a synthetic strategy in which the site selectivity can be controlled will be of great interest and concern.…”