Abstract
A one-pot approach for ortho-coupling of arenes with non-actived N-nucleophiles has been developed using sequential iron and copper catalysis. Regioselective ortho-activation of anisoles, anilines and phenols was achieved through iron(iii) triflimide catalysed iodination, followed by a copper(i)-catalysed, ligand-assisted coupling reaction with N-heterocycle, amide and sulfonamide-based nucleophiles. The synthetic utility of this one-pot, two-step method for the direct amination of ortho-aryl C-H bonds was demonstrated with the late-stage functionalisation of 3,4-dihydroquinolin-2-ones. This allowed the preparation of a TRIM24 bromodomain inhibitor and a series of novel analogues.
Highlights
In the last few decades, significant progress in the development of transition metal catalysed reactions has resulted in regioselective formation of aryl C–N bonds and the use of these processes for the general synthesis of pharmaceutically active compounds, organic materials and natural products.[1]
To avoid arene ring pre-functionalisation, more recent strategies have focused on ortho-directed dehydrogenative coupling of aryl C–H bonds with non-activated amines and amides using chelating auxiliary groups in the presence of oxidants such as oxygen or hypervalent iodine compounds.[5]
We recently reported a one-pot para-amination and amidation of activated arenes using sequential iron and copper catalysis.[10]
Summary
In the last few decades, significant progress in the development of transition metal catalysed reactions has resulted in regioselective formation of aryl C–N bonds and the use of these processes for the general synthesis of pharmaceutically active compounds, organic materials and natural products.[1]. Various anilines were subjected to the standard one-pot iron-catalysed activation and copper-catalysed coupling process and gave the ortho-substituted adducts (3a–3e) cleanly, in good yields (58–71%). Regioselective activation of arenes via iodination, using NIS and the super Lewis acid, iron(III) triflimide, followed by copper(I)-catalysed, ligand-assisted coupling with a range of N-nucleophiles gave the ortho-substituted products in good yields. Purification by flash column chromatography (hexane/diethyl ether, 4 : 1) gave N-(2-methoxy-5-methylphenyl)-1H-pyrazole (3f ) (0.067 g, 71%) as a colourless oil.
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