Redox-Triggered α-C–H Functionalization of Pyrrolidines: Synthesis of Unsymmetrically 2,5-Disubstituted Pyrrolidines

Abstract

By using o-benzoquinone as an internal oxidant, the regio- and diastereoselective functionalization of the secondary over the tertiary α-C-H bond of 2-substituted pyrrolidines is first realized. Subsequent intermolecular addition of a nucleophile to the generated N,O-acetal and cleavage of the aromatic substituent leads to 2,5-disubstituted pyrrolidines.

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

“…When the ratio of rac-1a and 2a was 4:1 at 0 C, the yield and enantioselectivity were highest (Table 1, entry 19, 83% yield and 97% ee). Thus, the following optimized reaction conditions were obtained: 10 mol % of Cu(OTf) 2 , 12 mol % of L3, 1.0 equivalent of 2a, and 4.0 equivalents of 1a in DCM at 0 C (Table 1, entry 19).…”

“…[6][7][8][9] In addition, these structures are often used as key intermediates in organic synthesis. [10][11][12][13][14][15][16][17][18][19] Therefore, efficient methods for constructing complex chiral heterocycles are in high demand.…”

Classical-Reaction-Driven Stereo- and Regioselective C(sp3)-H Functionalization of Aliphatic Amines

“…[40] Qu et al developed similar redox-neutral CAH oxygenation of pyrrolidine using 3,5-di-tert-butyl-o-benzoquinone. [41] During the optimization of the direct CAH oxygenation reaction, we observed that N-benzylated pyrrolidine 68 was formed in addition to the desired oxazine. It was further observed that the reaction could be drawn to provide Nbenzylated pyrrolidine 68 by increasing the stoichiometry of pyrrolidine.…”

“…This strategy was extended by the same group for the α‐CH sulfenylation of aliphatic amines 40. Qu et al developed similar redox‐neutral CH oxygenation of pyrrolidine using 3,5‐di‐ tert ‐butyl‐ o‐ benzoquinone 41…”

Amine Functionalization through Sequential Quinone‐Catalyzed Oxidation/Nucleophilic Addition

“…Krische has demonstrated that transfer hydrogenation can be used to functionalize secondary amines (Scheme b) . Stoichiometric methods that enable the functionalization of secondary and tertiary, amines have also been reported. Dehydrogenative cross‐coupling has also been heavily utilized to enable the functionalization of such substrates , .…”