Nitrosobenzene‐Enabled Chiral Phosphoric Acid Catalyzed Enantioselective Construction of Atropisomeric N‐Arylbenzimidazoles

Abstract

Described herein is an imidazole ring formation strategy for the synthesis of axially chiral N-arylbenzimidazoles by means of chiral phosphoric acid catalysis. Two sets of conditions were developed to transform two classes of 2naphthylamine derivatives into structurally diverse N-arylbenzimidazole atropisomers with excellent chemo-and regioselectivity as well as high levels of enantiocontrol. It is worth reflecting on the unique roles played by the nitroso group in this domino reaction. It functions as a linchpin by first offering an electrophilic site (N) for the initial C À N bond formation while the resulting amine performs the nucleophilic addition to form the second CÀN bond. Additionally, it could facilitate the final oxidative aromatization as an oxidant. The atropisomeric products could be conveniently elaborated to a series of axially chiral derivatives, enabling the exploitation of N-arylbenzimidazoles for their potential utilities in asymmetric catalysis.

Asymmetric Synthesis of Axially Chiral C−N Atropisomers

“…Furthermore, an atroposelective synthesis of axially chiral N ‐arylbenzimidazoles 151 have also been very recently reported by Tan and co‐workers [76] . The strategy relies on the use of chiral phosphoric acid (CPA) catalysis for the C−N bond formation between 2‐ naphthylamine derivatives 149 and nitrosoarenes 150 as the electrophilic amination reagent (Scheme 45).…”

Recent advances in the catalytic asymmetric construction of atropisomers by central-to-axial chirality transfer

“…In 2021, the Tan group described an atroposelective synthesis of N -arylbenzimidazoles 72 via CPA-catalyzed annulations of 2-naphthylamines 70 and nitrosobenzenes 71 73 (Scheme 17). The niroso group in 71 , herein, served not only as an electrophilic and nucleophilic site at the nitrogen atom for C–N bond formation, but also as an effective oxidant to promote the oxidative aromatization to achieve central-to-axial chirality transfer.…”

Enantioselective Synthesis of Axially Chiral Benzimidazoles ­Bearing a C–N axis via Pd-Catalyzed Buchwald–Hartwig ­Amination

“…Recently, Tan and co-workers furnished the asymmetric synthesis of axially chiral benzimidazoles via the annulation of 2-naphthylamines and nitrosobenzenes (Scheme 3). 19 The stereocontrol was achieved with the aid of bifunctional chiral phosphoric acids. The mechanism was depicted as follows, the reaction initiated with the nucleophilic attack of 2-naphthylamines to nitrosobenzene to give intermediate I. Dehydration of I delivered II, which could undergo 1,5-hydrogen shift to give IV.…”

“…16 However, few efforts are devoted to the asymmetric synthesis of axial C-N benzimidazole atropisomers due to its decreased configurational stability. [17][18][19] In 2018, Toste and Miller pioneered the asymmetric synthesis of C-N benzimidazole atropisomers through intramolecular cyclodehydration of ortho-substituted anilines (Scheme 1). 17 The utility of hydrogen-bond-donor catalyst, such as phosphothreonine-embedded peptidic phosphoric acids ('pThr-type' CPA) and C 2 -symmetric chiral phosphoric acids ('C 2 -type' CPA), helped to furnish the construction of benzimidazole bearing a C-N axis.…”