Acylation of Pyrroles and their Free (N‐H)‐Derivatives via Palladium‐Catalyzed Carbopalladation of Nitriles

Abstract

An efficient regioselective synthesis of 2-acylpyrroles via palladium-catalyzed addition of pyrroles with benzonitriles and subsequent hydrolysis is developed. The direct acylation reaction of protected as well as (NH)-free pyrroles proceeded smoothly to afford 2-acylpyrrole scaffolds of high biological interest.

[3 + 2 + 1] Pyridine Skeleton Synthesis Using Acetonitrile as C4N1 Units and Solvent

“…The desired product 2,4,6-triphenyl pyridine 3aa was isolated in 23% yield using Pd­(OAc) 2 as the catalyst, K 2 S 2 O 8 as the oxidant, and acetonitrile as the reactant/solvent (see Table , entry 1). In view of the facts that the bidentate nitrogen ligands were suitable for most carbopalladation reactions of aliphatic nitriles, 2,2′-bipyridine L 1 was added as the ligand and the yield of 3aa enhanced obviously (entry 2). − Encouraged by this result, we then surveyed various oxidants, and the best outcome in terms of efficiency was obtained in case of 1-fluoro-2,4,6-trimethylpyridin-1-ium trifluoromethanesulfonate O 1 , which is a kind of F + oxidant and can be applied to control selective reductive elimination of high valent palladium intermediates (entries 3–5). , It is worth noting that no desired product was obtained without any oxidant (entry 6). A few different palladium catalysts including palladium­(II) and palladium(0) salts were tested of which Pd­(OAc) 2 still was the most successful (entries 7–9).…”

“…Nitriles are one of the most versatile scaffolds in both synthetic and medicinal chemistry. , It is well known that the nitrile group is generally inert in organometallic reactions, and compounds such as acetonitrile are commonly employed as solvents in many catalytic reactions . Since the pioneering work of the Larock group, transition-metal-catalyzed nucleophilic addition reactions to nitriles had offered an attractive route to construct carbon–carbon and carbon–heteroatom bonds over the past decade. − The intramolecular carbopalladation of aliphatic nitriles using arylboronic acids, potassium aryltrifluoroborates, benzoic acids, arene, heteroarene, − sodium arylsulfinates, arylhydrazines, and arylsulfonyl hydrazides as coupling partners for the synthesis of ketones and derivatives via the ketimine intermediate has been extensively reported. However, the nitrogen atom of aliphatic nitriles has not found application in the construction of N-heterocycles precisely because of the hydrolysis of the ketimine intermediate.…”

Recent Advances in Functionalization of Pyrroles and their Translational Potential

“…The unusual acylation of (N−H)‐pyrroles under moderate reaction conditions and with no obligation for protection of the NH group was accomplished (Scheme 27). [39] Optimized condition required 5 mol% of Pd(OAc) 2 , 20 mol% of bpy ligand in AcOH/H 2 O/DME solvent system at 80 °C for 24 h. This methodology was via ble with benzonitriles having electron‐donating and electron‐withdrawing groups under the introduced catalytic framework to manage the synthesis of biologically intriguing 2‐acylpyrroles.…”

Recent Advances in Transition-Metal-Catalyzed C–H Addition to Nitriles

“…Furthermore, in 2014, Jafarpour and co-workers demonstrated an efficient regioselective preparation of 2acylpyrroles via palladium-catalyzed addition of pyrroles to benzonitriles by using Pd(OAc) 2 (5 mol%) and bpy (20 mol%) in HOAc/H 2 O/DME at 80 °C as the optimal reaction condi-tions (Scheme 12). 19 Pyrrole derivatives, such as N-methylpyrrole, N-benzylpyrrole and free NH-pyrroles, and various benzonitriles were employed in these Pd-catalyzed direct acylation reactions, which provided 2-acylpyrroles 7 in moderate to good yields. However, with respect to aliphatic nitriles, only benzyl nitrile gave the desired product in a moderate yield.…”