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.
Tetrabutylammonium Azide. In Encyclopedia of Reagents for Organic Synthesis.-. In Encyclopedia of Reagents for Organic Synthesis which has been published in final form at
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