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Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines.

Accepted version
Peer-reviewed

Type

Article

Change log

Abstract

Molecules displaying an α-trialkyl-α-tertiary amine motif provide access to an important and versatile area of biologically relevant chemical space but are challenging to access through existing synthetic methods. Here, we report an operationally straightforward, multicomponent protocol for the synthesis of a range of functionally and structurally diverse α-trialkyl-α-tertiary amines, which makes use of three readily available components: dialkyl ketones, benzylamines, and alkenes. The strategy relies on the of use visible-light-mediated photocatalysis with readily available Ir(III) complexes to bring about single-electron reduction of an all-alkyl ketimine species to an α-amino radical intermediate; the α-amino radical undergoes Giese-type addition with a variety of alkenes to forge the α-trialkyl-α-tertiary amine center. The mechanism of this process is believed to proceed through an overall redox neutral pathway that involves photocatalytic redox-relay of the imine, generated from the starting amine-ketone condensation, through to an imine-derived product. This is possible because the presence of a benzylic amine component in the intermediate scaffold drives a 1,5-hydrogen atom transfer step after the Giese addition to form a stable benzylic α-amino radical, which is able to close the photocatalytic cycle. These studies detail the evolution of the reaction platform, an extensive investigation of the substrate scope, and preliminary investigation of some of the mechanistic features of this distinct photocatalytic process. We believe this transformation will provide convenient access to previously unexplored α-trialkyl-α-tertiary amine scaffolds that should be of considerable interest to practitioners of synthetic and medicinal chemistry in academic and industrial institutions.

Description

Keywords

3402 Inorganic Chemistry, 3405 Organic Chemistry, 34 Chemical Sciences

Journal Title

J Am Chem Soc

Conference Name

Journal ISSN

0002-7863
1520-5126

Volume Title

143

Publisher

American Chemical Society (ACS)

Rights

All rights reserved
Sponsorship
Engineering and Physical Sciences Research Council (EP/S024220/1)
Engineering and Physical Sciences Research Council (EP/S020292/1)
Engineering and Physical Sciences Research Council (2276993)
AstraZeneca-Cambridge PhD programme; Royal Society Wolfson Merit Award