Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated δ C–H Cyanation

Abstract

Piperidines are the most prevalent heterocycle found in medicines. Yet, although they are often chiral, there remain no robust methods for their asymmetric syntheses. To solve this challenge, we have interrupted the century-old Hofmann-Lö ffler-Freytag (HLF) reaction to afford this privileged heterocycle. The catalytic, regio-, and enantioselective d C-H cyanation of acyclic amines described here, incorporates a carbonyl equivalent selectively at the d position. This d C-H cyanation is enabled by a chiral Cu catalyst, which both initiates and terminates intramolecular hydrogen atom transfer (HAT) by an N-centered radical relay mechanism. The broad scope and utility of this highly enantioselective method for d C-C formation is presented, as well as conversion of the resulting enantioenriched d-amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio-selectivity of this HAT mechanism are also included to enable extension to other stereoselective d C-H functionalizations.

Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates

“…In addition, the reaction has been extended to intermolecular benzylic C(sp 3 )-H arylation 65 and alkynylation 66 by replacing the cyanation reagent TMSCN (trimethylsilyl cyanide) with aryl boronic acid and alkynyl silane, respectively. Furthermore, the groups led by Liu, Nagib, Wang, and Yu have independently reported enantioselective benzylic C(sp 3 )-H cyanation [67][68][69][70] and alkynylation 71 by merging oxidative radical precursors into substrates, which upon SET reduction provides alkoxy, sulfonamidyl, or amidyl radicals for intramolecular 1,5-HAA with high regioselectivity. At the same time, Liu's group has also found mildly oxidative N-fluoroamide is well compatible with their Cu(I)/ cinchona alkaloid-derived N,N,P-ligand catalyst 16 (Fig.…”

Benzylic C–H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

“…Cu-catalyzed radical-relay reactions that use N-uorobenzenesulfonimide (NFSI) as the oxidant have expanded rapidly in recent years 19,[29][30][31][32][33][34][35][36][37][38][39] and offered a possible strategy to achieve C-H isocyanation as these methods oen support oxidative coupling with the C-H substrate as the limiting reagent. Several mechanistic features of these reactions merit consideration.…”

Recent Advances in Copper-Catalyzed Radical C–H Bond Activation Using N–F Reagents

“…Importantly, in a 2019 contribution Nagib and co-workers 32 developed an enantioselective -Csp 3 -H bond cyanation of N-fluorotosylamides, using TMSCN and a chiral copper complex as the catalyst (Scheme 21a). This conversion of N-fluorotosylamides to enantioenriched -amino nitriles constituted the first example of a highly asymmetric variant of a Hofmann-Löffler-Freytag reaction.…”