Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu‐Catalyzed Atroposelective Aryl Amination

Abstract

N−C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal‐catalyzed atroposelective N‐arylations have been described. Herein, we disclose an unprecedented Cu‐catalyzed atroposelective N−C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N−C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post‐modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.

Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu‐Catalyzed Atroposelective Aryl Amination

“…The absolute aR configuration of 5 was determined based on X-ray crystallography (Figure 3). [19] Notably, the crystal structure shows hydrogen bonding between the N atom of indoline and the amide motif, which is consistent with the particular importance of this directing group (DG) for the efficiency of the reaction. Furthermore, two chiral molecules are present in a chiral unit, and intermolecular hydrogen bonding between -NH 2 and the O atom is evidenced.…”

Rhodium‐Catalyzed Atroposelective Construction of Indoles via C−H Bond Activation

“…They are alternatively accessed by metal catalysis (Scheme 1) following two synthetic strategies. Metal‐catalyzed arylation of an existing indole ring at the 1‐, [3] 2‐, [4] and 3‐positions [5] (Scheme 1 a) using hypervalent iodine reagents, [3] aryl halides, [4] and quinones [4] induced axial chirality. In addition, functionalization of an arene [6] or olefin [7] group tethered to an indole also generated a C−N or C−C chiral axis.…”

Enantioselective Synthesis of Atropisomeric Biaryls by Pd‐Catalyzed Asymmetric Buchwald–Hartwig Amination

“…[12] Very recently, Wencel-Delord and co-workers reported the first case of a more challenging intermolecular atroposelective Ullmann-type N À C coupling reaction by utilizing C(sp 2 )hypervalent iodine reagents as carbon substrates and substituted indolines as nitrogen substrates (Scheme 1 B c). [13] Despite these contributions, the enantioselective synthesis of NÀC biaryl atropisomers by metal-catalyzed aryl amination remains an unexplored field; however, the optically active biaryl products formed are highly valuable. We herein describe the Pd-catalyzed intramolecular N À C cross-coupling reactions of amidines [14] for the highly enantioselective synthesis of biaryl atropisomers to obtain NÀC axially chiral biaryl atropisomers by Buchwald-Hartwig amination (Scheme 1 C).…”