Palladium-Catalyzed Direct Intermolecular Amination of Unactivated Methylene C(sp³)–H Bonds with Azodiformates via Bidentate-Chelation Assistance

Abstract

An efficient and convenient method enabling direct amination of unactivated methylene C(sp 3 )−H bonds to form C−N bonds with azodiformates as amino source is described. This method highlights the emerging strategy of unactivated methylene as versatile functional groups in organic synthesis and provides a strategy to construct functionalized C−N bonds for the synthesis of complex molecules.

Transition Metal‐Controlled Direct Regioselective Intermolecular Amidation of C−H Bonds with Azodicarboxylates: Scope, Mechanistic Studies, and Applications

“…Our interest in this particular regioselective C−H amidation originated from our recent studies . We discovered that azodicarboxylates can serve as unique amino sources in Pd‐catalyzed amidation reactions of unactivated β‐C( sp 3 )−H bonds under relatively mild conditions using 2‐(pyridine‐2‐yl)isopropyl (PIP) as N , N‐ bidentate directing groups.…”

“…Although azodicarboxylates have been exploited in various organic reactions, surprisingly, they are usually used as carbonyl sources in directing group‐mediated C−H carbonylation reactions (Scheme b). In 2017, our group reported the first example of a palladium‐catalyzed, bidentate‐chelation‐assisted intermolecular C( sp 3 )−H amination of unactivated methylene using azodicarboxylates as amino source (Scheme a). Although this advance has received much attention, it has several limitations, including low yields and requiring high catalyst loading, the reaction must be further optimized to achieve regio‐ and stereoselectivity beyond the level available with substrate control…”

Rhodium‐Catalyzed Selective C−H Bond Functionalization of Quinolines

“…[61] In 2008, this substrate first time used for sp 2 and sp 3 carbonylation, [62] and in 2017, sp 3 amination of 8methylquinoline was reported by the Zang group under palladium catalysis. [63] Kim and coworkers keeping in mind the importance of C(sp 3 )À H functionalization utilized the azodicarboxylates for the chemoselective amination of 8-methylquinolines. The method did not apply to the secondary sp 3 CÀ H bond.…”

Nickel, Cobalt and Palladium Catalysed C−H Functionalization of Un‐Activated C(sp3)−H Bond

“…Using the same reaction protocol author also carried out more than one substituents present on the aryl iodides to give good yields of corresponding non‐natural amino acids. In same line of β‐C(sp 3 )−H activation, Zhang and coworker in the year 2017, described the formation of C−N bonds from azodiformates as new amino source using palladium‐catalyzed bidentate‐chelation assistant intermolecular direct amination of inactivated methylene C(sp 3 )−H bonds . Employing 0.2 mmol of 2‐(pyridin‐2‐yl) isopropyl (PIP) as bidentate ligand to react with 2 equiv.…”