Jump to main content
Jump to site search

Issue 3, 2016
Previous Article Next Article

Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

Author affiliations

Abstract

The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C–H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.

Graphical abstract: Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

Back to tab navigation

Supplementary files

Article information


Submitted
11 Nov 2015
Accepted
20 Nov 2015
First published
03 Dec 2015

This article is Open Access

Org. Biomol. Chem., 2016,14, 1065-1090
Article type
Paper
Author version available

Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

B. S. Pilgrim, A. E. Gatland, C. H. A. Esteves, C. T. McTernan, G. R. Jones, M. R. Tatton, P. A. Procopiou and T. J. Donohoe, Org. Biomol. Chem., 2016, 14, 1065 DOI: 10.1039/C5OB02320C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.


Social activity

Search articles by author

Spotlight

Advertisements