Organocatalytic Enantioselective Aza‐Friedel–Crafts Reaction of Cyclic Ketimines with Pyrroles using Imidazolinephosphoric Acid Catalysts

Abstract

Organocatalytic enantioselective aza-Friedel-Crafts reactions of cyclic ketimines with pyrroles or indoles were catalyzed by imidazoline/phosphoric acid catalysts. The reaction was applied to various 3H-indol-3-ones to afford products in excellent yields and enantioselectivities. The chiral catalysts can be recovered by a single separation step using column chromatography and are reusable without further purification. Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.

Organocatalytic Asymmetric Transformations Involving the Cyclic Imine Moiety in Indole and Isoindole Related Heterocycles

“…The bis(imidazoline)‐phosphoric acid catalyst Cat. 9 which was developed by the Nakamura group was identified as a privileged bifunctional organocatalyst for reactions between 2‐aryl‐3 H ‐indol‐3‐ones 1c and non‐protected pyrroles 28 to produce 29 , as shown by the same group in 2016 (Scheme ) . Some salient features of this aza‐FC reaction include low catalyst loading (2 mol%), broad substrate scope, excellent chemical yields and enantioselectivities (90–99% ee ), as well as scalability and ability to recycle the catalyst.…”

Organocatalytic Enantioselective Friedel‐Crafts Alkylation Reactions of Pyrroles

“…Thus, N ‐unprotected pyrroles 1 reacted with 2‐substituted‐ 3H ‐indol‐3‐ones 72 in the presence of chiral BPA XXIX to afford indolinones 73 bearing a quaternary stereocenter in excellent yields and ee values (Scheme 34). [54] A wide variety of substitution is well tolerated both in the pyrroles and starting ketimines, without compromising the enantioselectivity. However, only aromatic ketimines were used in the process.…”

Recent Advances in Metal‐ and Organocatalyzed Asymmetric Functionalization of Pyrroles

“…By employing 2 mol% of bis(imidazoline)phosphoric acid C-12 as the catalyst, the aza-Friedel-Crafts reaction of pyrroles 11 to 2-substituted-3H-indol-3-ones 28 proceeded smoothly at À 40 °C and afforded the desired α-functionalized pyrrole products 29 in good to excellent yield with excellent enantioselectivities (Scheme 10). [58] Although diverse substitution on the electrophilic partner (R 2 and R 3 ) could be well tolerated with unprotected pyrroles, the reaction with methylsubstituted pyrrole (R 1 =Me) failed to yield excellent enantioselectivities rather than gave moderate enantioselectivities (54% ee). Another useful application of the methodology was established by employing C-3-substituted pyrroles 30 as the nucleophile under the standard reaction condition with the temperature at À 60 °C to À 78 °C.…”