Atom transfer radical cyclisations of activated and unactivated N-allylhaloacetamides and N-homoallylhaloacetamides using chiral and non-chiral copper complexes

Andrew J. Clark; Floryan De Campo; Robert J. Deeth; Robert P. Filik; Sylvain Gatard; Nicola A. Hunt; Dominique Lastécouères; Gerard H. Thomas; Jean-Baptiste Verlhac; Hathaichanuk Wongtap

doi:10.1039/A909666C

Atom transfer radical cyclisations of activated and unactivated N-allylhaloacetamides and N-homoallylhaloacetamides using chiral and non-chiral copper complexes

Andrew J. Clark,*^a Floryan De Campo,^b Robert J. Deeth,^a Robert P. Filik,^a Sylvain Gatard,^b Nicola A. Hunt,^a Dominique Lastécouères,^b Gerard H. Thomas,^c Jean-Baptiste Verlhac*^b and Hathaichanuk Wongtap^a

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^a Department of Chemistry, University of Warwick, Coventry, UK

^b Laboratoire de Chimie Organique et Organométallique (UMR 5802 CNRS), Université Bordeaux I, 351 cours de la Libération, Talence cedex, France

^c Knoll Pharmaceuticals, Research and Development Department, Pennyfoot Street, Nottingham, UK

Abstract

Activated N-tosyl-2,2,2-trichloroacetamide 6a, N-benzyl-2,2,2-trichloroacetamide 6d, 2,2-dichloroacetamides 6b–c and 6e–f and 2-monohaloacetamides 11a–g undergo efficient 5-exo atom transfer radical cyclisations at room temperature mediated by CuCl or CuBr in the presence of tris(N,N-dimethylaminoethylene)amine 3 (trien-Me₆). The efficiency and stereoselectivity of these cyclisations was found to be greater than existing published atom transfer procedures based upon CuCl(bipyridine), RuCl₂(PPh₃)₃ and CuCl(TMEDA)₂. The product distribution for the cyclisation onto alkyne 11g was found to be solvent dependent. Attempts to make larger ring sizes by endo cyclisation of N-tosylacetamides 19a–c led to a competing 5-exoipso aromatic substitution into the N-tosyl group followed by re-aromatisation and loss of SO₂ to furnish an amidyl radical. Cyclisation of N-homoallylacetamides 25a–d proceeded smoothly to give δ-lactams with a range of catalysts based upon ligands 2 and 26. The stereoselectivity of cyclisation to give γ lactams could be somewhat influenced by using chiral enantiopure copper complexes 28–30 suggesting that the reactions may involve metal-complexed radicals.

Journal of the Chemical Society, Perkin Transactions 1

Atom transfer radical cyclisations of activated and unactivated N-allylhaloacetamides and N-homoallylhaloacetamides using chiral and non-chiral copper complexes

Abstract

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Atom transfer radical cyclisations of activated and unactivated N-allylhaloacetamides and N-homoallylhaloacetamides using chiral and non-chiral copper complexes

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