Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

Abstract

Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N -arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.

Continuous Flow Preparation of Benzylic Sodium Organometallics

“…Fingolimod ( 5 ) and salmeterol ( 6 ) are among the 100 best selling drugs, both exceeding retail sales of 2 billion USD in 2020 [34] . The multiple scleroses therapeutics fingolimod ( 5 ) has previously been synthesized by various approaches [16b–d] . Most of them require transition metal catalyzed cross‐coupling reaction to introduce the octyl group.…”

Herstellung von benzylischen Natrium‐Metallorganylen im kontinuierlichen Durchfluss

“…USD [34] . Bisher wurde das Multiple‐Sklerose‐Therapeutikum Fingolimod ( 5 ) durch verschiedene Methoden synthetisiert, von denen die meisten eine übergangsmetalkatalysierte Kreuzkupplungsreaktion zur Einführung der Octylkette benötigten [16b–d] . Wir überlegten uns eine Synthese ausgehend von kostengünstigem p ‐Xylol ( 3 c ).…”

Tantalum Ureate Complexes for Photocatalytic Hydroaminoalkylation

“…Recently, the Cresswell group successfully overcame this challenge by using a hydrogen-atom-transfer (HAT) reagent together with organic photocatalysts to achieve styrene hydroaminoalkylation with unprotected alkylamines. 46 Thermally promoted ETM catalyzed hydroaminoalkylation are efficient with unactivated alkenes and unprotected amines, but high temperatures are usually required. Meanwhile, early transition metal complexes featuring M-Csp³ bonds are known to undergo light induced homolytic cleavage.…”