Remote C6-Selective Ruthenium-Catalyzed C-H Alkylation of Indole Derivatives via σ-Activation

Jamie A. Leitch, Claire L. McMullin, Mary F. Mahon, Yunas Bhonoah, Christopher G. Frost

Research output: Contribution to journalArticle

58 Citations (Scopus)
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Abstract

The site-selective functionalization of an indole template offers exciting possibilities for the derivatization of molecules with useful biological properties. Herein, we report the remote C6-selective C-H alkylation of indole derivatives enabled by dual cyclometalation/redox ruthenium catalysis. Remote alkylation was achieved using N-pyrimidinyl indoles with an ancillary ester directing group at the C3 position. This ancillary directing group proved pivotal to reactivity at C6, with yields up to 92% achieved. A one-pot procedure to install this directing group followed by remote C6 functionalization has also been reported; both processes are shown to proceed via ruthenium redox catalysis. Computationally calculated Fukui indices elucidated that the C6 position was the most reactive vacant C-H site toward potential functionalization. When this investigation was coupled with deuterium incorporation studies, a C2-cyclometalation/remote σ-activation pathway was deduced.

Original languageEnglish
Pages (from-to)2616-2623
Number of pages8
JournalACS Catalysis
Volume7
Issue number4
Early online date6 Mar 2017
DOIs
Publication statusPublished - 7 Apr 2017

Fingerprint

Ruthenium
Alkylation
Catalysis
Chemical activation
Derivatives
Indoles
Deuterium
Esters
Molecules
indole
Oxidation-Reduction

Keywords

  • heteroaromatics
  • homogeneous catalysis
  • indole
  • remote functionalization
  • ruthenium

ASJC Scopus subject areas

  • Catalysis

Cite this

Remote C6-Selective Ruthenium-Catalyzed C-H Alkylation of Indole Derivatives via σ-Activation. / Leitch, Jamie A.; McMullin, Claire L.; Mahon, Mary F.; Bhonoah, Yunas; Frost, Christopher G.

In: ACS Catalysis, Vol. 7, No. 4, 07.04.2017, p. 2616-2623.

Research output: Contribution to journalArticle

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AU - Bhonoah, Yunas

AU - Frost, Christopher G.

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AB - The site-selective functionalization of an indole template offers exciting possibilities for the derivatization of molecules with useful biological properties. Herein, we report the remote C6-selective C-H alkylation of indole derivatives enabled by dual cyclometalation/redox ruthenium catalysis. Remote alkylation was achieved using N-pyrimidinyl indoles with an ancillary ester directing group at the C3 position. This ancillary directing group proved pivotal to reactivity at C6, with yields up to 92% achieved. A one-pot procedure to install this directing group followed by remote C6 functionalization has also been reported; both processes are shown to proceed via ruthenium redox catalysis. Computationally calculated Fukui indices elucidated that the C6 position was the most reactive vacant C-H site toward potential functionalization. When this investigation was coupled with deuterium incorporation studies, a C2-cyclometalation/remote σ-activation pathway was deduced.

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