Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via Palladium Catalyzed Intramolecular Amination of C(sp³)–H and C(sp²)–H Bonds at γ and δ Positions

Abstract

Efficient methods have been developed to synthesize azetidine, pyrrolidine, and indoline compounds via palladium-catalyzed intramolecular amination of C-H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates. These methods feature relatively a low catalyst loading, use of inexpensive reagents, and convenient operating conditions. Their selectivities are predictable. These methods highlight the use of unactivated C-H bond, especially the C(sp(3))-H bond of methyl groups, as functional groups in organic synthesis.

Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group

“…In contrast, transition metal-catalyzed site-selective functionalization of primary alkylamines is rare, in part due to the strong binding properties of amines to a metal, and thus the formation of stable bis(amine) metal complexes which disfavors the C−H bond cleavage of an sp 3 carbons. To weaken the coordination of amines to a metal, an electron-withdrawing group is often used to attach to the nitrogen atom of an alkylamine (Fig. 1e and 1f) [25][26][27][28][29][30] . However, the removal of the auxiliary moiety after C−H bond functionalization is often problematic.…”

Silver-catalysed direct amination of unactivated C–H bonds of functionalized molecules

“…Primary C-H bonds could be accessed only in cases of conformational bias 38,39 . To approach the primary selectivity of direct amination, Chen and Daugulis groups successfully developed a Pd-catalysed cyclization to specific ring systems by using a directing strategy while the manipulation of protecting group by multistep transformations limited its applications [40][41][42] To achieve the primary selectivity to construct the abundant five-membered heterocyclic products from easily available amine derivatives without the requirement of complicated directing groups, new strategies and new catalytic systems are highly desirable 43,44 . Notably, the compatibility with an array of the functionalities, the availability of the starting materials and the reliability of the new reaction system are important for potential applications.…”

Pd‐Catalyzed Synthesis of Nitrogen‐Containing Heterocycles

“…In 2012, Chen and coworkers developed the palladium-catalyzed intramolecular amination of C(sp 3 )-H at γ and δ positions to synthesize a series of nitrogen-containing heterocycles [15], including azetidine (Scheme 2.11), pyrrolidines, and indolines. With the optimal conditions, using catalytic Pd(OAc) 2 , an oxidant (PhI(OAC) 2 , 2.5 equiv.)…”