Cargando…

A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and smallmolecule biological probes(1,2) continues to stimulate enormous efforts towards their streamlined synthesis(3–9). Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl r...

Descripción completa

Detalles Bibliográficos
Autores principales: Kumar, Roopender, Flodén, Nils J., Whitehurst, William G., Gaunt, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116815/
https://www.ncbi.nlm.nih.gov/pubmed/32268340
http://dx.doi.org/10.1038/s41586-020-2213-0
_version_ 1783514246836912128
author Kumar, Roopender
Flodén, Nils J.
Whitehurst, William G.
Gaunt, Matthew J.
author_facet Kumar, Roopender
Flodén, Nils J.
Whitehurst, William G.
Gaunt, Matthew J.
author_sort Kumar, Roopender
collection PubMed
description The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and smallmolecule biological probes(1,2) continues to stimulate enormous efforts towards their streamlined synthesis(3–9). Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl reductive amination(3): comprising two elementary steps, condensation of a secondary alkylamine with an aliphatic aldehyde forms an all alkyl-iminium ion, which is reduced by a hydride reagent. Chemists have sought to develop direct strategies for a ‘higher order’ variant of this reaction via the union of an alkyl fragment with an in-situ generated all alkyl-iminium ion(10–14). However, despite more than 70 years of research, the successful realization of a ‘carbonyl alkylative amination’ has remained elusive. Herein, we report that a practical and general solution can be accomplished by the addition of alkyl-radicals to all alkyl-iminium ions. The process is facilitated by visible-light and a silane reducing agent, which, together with the other reaction components, trigger a distinct radical initiation step to establish a chain process. An attractive feature of this operationally straightforward, metal-free and modular transformation is the unbiased nature of tertiary amines that arise from the traceless union of aldehydes and secondary amines with alkyl-halides. As such, the structural and functional diversity within these classes of abundant feedstocks provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.
format Online
Article
Text
id pubmed-7116815
institution National Center for Biotechnology Information
language English
publishDate 2020
record_format MEDLINE/PubMed
spelling pubmed-71168152021-02-24 A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light Kumar, Roopender Flodén, Nils J. Whitehurst, William G. Gaunt, Matthew J. Nature Article The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and smallmolecule biological probes(1,2) continues to stimulate enormous efforts towards their streamlined synthesis(3–9). Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl reductive amination(3): comprising two elementary steps, condensation of a secondary alkylamine with an aliphatic aldehyde forms an all alkyl-iminium ion, which is reduced by a hydride reagent. Chemists have sought to develop direct strategies for a ‘higher order’ variant of this reaction via the union of an alkyl fragment with an in-situ generated all alkyl-iminium ion(10–14). However, despite more than 70 years of research, the successful realization of a ‘carbonyl alkylative amination’ has remained elusive. Herein, we report that a practical and general solution can be accomplished by the addition of alkyl-radicals to all alkyl-iminium ions. The process is facilitated by visible-light and a silane reducing agent, which, together with the other reaction components, trigger a distinct radical initiation step to establish a chain process. An attractive feature of this operationally straightforward, metal-free and modular transformation is the unbiased nature of tertiary amines that arise from the traceless union of aldehydes and secondary amines with alkyl-halides. As such, the structural and functional diversity within these classes of abundant feedstocks provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines. 2020-05-01 2020-04-08 /pmc/articles/PMC7116815/ /pubmed/32268340 http://dx.doi.org/10.1038/s41586-020-2213-0 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kumar, Roopender
Flodén, Nils J.
Whitehurst, William G.
Gaunt, Matthew J.
A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
title A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
title_full A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
title_fullStr A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
title_full_unstemmed A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
title_short A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
title_sort general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116815/
https://www.ncbi.nlm.nih.gov/pubmed/32268340
http://dx.doi.org/10.1038/s41586-020-2213-0
work_keys_str_mv AT kumarroopender ageneralcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT flodennilsj ageneralcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT whitehurstwilliamg ageneralcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT gauntmatthewj ageneralcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT kumarroopender generalcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT flodennilsj generalcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT whitehurstwilliamg generalcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight
AT gauntmatthewj generalcarbonylalkylativeaminationfortertiaryaminesynthesisfacilitatedbyvisiblelight