Copper‐Catalyzed Site‐Selective Oxidative C−C Bond Cleavage of Simple Ketones for the Synthesis of Anilides and Paracetamol

Abstract

A copper-catalyzed approach for the N-acylation of anilines with acetone and acetophenones via CÀC bond cleavage is described. Under the developed conditions both CHCl 3 and CH 2 Cl 2 were identified as potential C1-source to promote the transformation. The reaction features a site selective CÀC bond cleavage to install the amide moieties with high functional-group compatibility and wide substrate scope. The developed method avoids the use of sensitive and narcotic agents. The method also represents an excellent complement to the previous protocols with lower E-factor (13.91 mg/1 mg) than current industrially used method (E-factor 17.54 mg/1 mg). The developed approach has also been extended for the effective preparation of pyridine derivatives and paracetamol in gram scale. The course of the reaction was monitored by 1 H NMR as a preliminary investigation of the reaction mechanism. recent years under the influence of transition-metal catalysis. [24] At present the most welcome approaches for the preparation of anilides via CÀC bond cleavage were attempted using a-nitro ketones (Scheme 1a), [21] 1,3-diketones (Scheme 1b) [22] and using a combination of carbodiimides and carbonyl derivatives (Scheme 1c) [23] as starting materials. Although, these methods are benign and well examined, they are limited by their narrow scope, use of activated 1,3-diketones as substrates and in few cases the use of hazardous reagents, radical initiators, and expensive catalysts. These limitations lead us to develop of convenient catalytic approach for the engineering of anilide functionalities using simple ketones and inexpensive methods. Here we describe an example of Cucatalyzed site-selective oxidative C(sp 3 )ÀC(sp 2 ) or C(sp 2 )ÀC(sp 2 ) bond cleavage of acetone and acetophenones to accomplish a facile approach for the synthesis of anilide derivatives (Scheme 1d). The developed protocol features high functional-group compatibility and wide substrate scope under the influence of CHCl 3 or CH 2 Cl 2 as C1-source. Results and DiscussionScheme 4. Facile access towards paracetamol (3 p) using acetone (2 a) as acetylating agent (in gram scale) Scheme 5. Scope of the 1,3-dicarbonyls 5 a-e as acetylating agent via Cu(II)-catalyzed CÀC bond cleavage. Scheme 6. Plausible mechanism for the Cu(II)-catalyzed CÀC bond cleavage.

Disulfide-Catalyzed Iodination of Electron-Rich Aromatic Compounds

“…The NMR spectrum was identical to that previously reported. 58 N-(4-Chlorophenyl)acetamide/N-(2-chlorophenyl)acetamide (2y/2y′ 3.5/1). Acetanilide (81.1 g, 0.6 mmol), bis(4-methoxyphenyl) disulfide 3c (1.7 mg, 6 μmol), and DBDMH (118.2 mg, 0.6 mmol) were reacted in acetonitrile (2 mL) for 20 min to afford 2y (64.0 mg, 63% yield) and 2y′ (18.0 mg, 18%), which were purified by flash column chromatography (hexane/acetone = 3:2) as a white solid.…”

Ruthenium(ii)-catalyzed chemoselective deacylative annulation of 1,3-diones with sulfoxonium ylides via C–C bond activation

“…In the past decade, chemoselective C–C(CO) bond cleavage has been extensively studied by employing the strategies of chelation assistance,2 ring-strain release,3 and aromatization 4. However, the selective cleavage of unstrained C–C(CO) moieties without an auxiliary directing group still remains an unmet challenge 5,6. Recently, transition metal-catalyzed C–C(CO) bond functionalization of 1,3-diones has been achieved by Jiao,6 a Bolm,6 b Peng,6 c and Wu 6 d .…”

Copper‐Catalyzed [2+2+1+1] Annulation for the Regioselective Synthesis of 2,6‐Diarylpyridines via C1‐Insertion and Subsequent Cyclization

“…Having previously worked on identical scaffolds, we began our initial experiments by taking propylamine ( 1 a ) and acetophenone ( 2 a ) as the model substrates. When the reactions were carried out between 1 a and 2 a using Cu(I)‐salts such as CuBr and CuTC (copper(I) thiophene‐2‐carboxylate) in DMSO at 120 °C, the product 2,6‐diphenylpyridine ( 3 aa ) can be isolated in 67 % and 61 % yields respectively (Table , Entries 1–2).…”