Direct α-C–H bond functionalization of unprotected cyclic amines

Abstract

Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N-H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (-)-solenopsin A.

Acid‐Catalyzed Cascade Reaction of 4‐Aminobutanal Derivatives with (Hetero)aromatic Nucleophiles: A Versatile One‐Pot Access to 2‐(Hetero)arylpyrrolidines.

“…As a rule, these reactions are based on α‐deprotonation of N ‐substituted pyrrolidines with organolithium compounds. Carbanions thus obtained are then involved into the Negishi cross‐coupling via a transmetallation with zinc halides followed by interaction with aryl halides . The other pathway within the same approach is a reaction of 2‐hydroxy‐, 2‐alkoxy‐ or 2‐acetoxypyrrolidines with organomagnesium or organolithium derivatives of aromatic compounds .…”

Mechanistic Investigations of an α-Aminoarylation Photoredox Reaction

“…For wavelengthdependent reactions, the cuvette was placed on a stir plate in front of a 950 W Xe arclamp (Oriel 66921) equipped with a monochromator (Spectral Products CM110) for 2 hours. After illumination, 0.25 mmol of triphenylmethane was added as an internal standard and the reaction allowed to stir for 30…”

“…[20][21][22][23][24][25][26][27][28] α-arylamines and substituted nitrogen heterocycles are important structural motifs in medicinal chemistry. 29 Generation of these motifs using latent sp 3 C-H bonds via cross-coupling of amines and aryl building blocks has attracted significant attention, 30,31 with photoredox reactions representing a particularly attractive approach. 32 The pioneering report on the photoredox generation of α-arylamines was first reported by Mac-Millan and coworkers, 33 though the use of cyanoarenes and α-amine radicals was subsequently generalized for a host of other photoredox transformations [34][35][36][37][38][39][40][41][42] and more recently to electrosynthetic chemistry.…”

Lewis Base Promoted Delayed Copper Catalysis: Borylative α-C-H Allylation of Alicyclic Amines

“…bearing contiguous quaternary and tertiary stereocentres. Gratifyingly, this method could be extended to other alicyclic amine frameworks such as piperidine (15,16), piperazine (17), pyrrolidine (18) and azepine (19), obtaining in all cases the product in good yield with perfect regio-and diastereoselectivity. Of note is the reaction with 4methylpiperidin-1-yl benzoate which afforded 16 bearing three new stereocentres which were generated with total stereocontrol.…”

“…16,17 Recently, Seidel and co-workers reported a method for the in-situ generation of alicyclic imines based on the reduction of a sacrificial ketone hydride acceptor by the corresponding N-lithiated amine. 18,19 The cyclic imine can then be trapped by an organolithium compound 18 or a Grignard reagent using Lewis acid activation, 19 thus resulting in a net α-C-H functionalization ( Figure 1B). Although this method represents an interesting entry to α-functionalized secondary alicyclic amines, cryogenic temperatures are required, and the stoichiometric use of organometallic reagents can impose extra steps associated to the preparation and purification of these sensitive compounds.…”