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

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-Me-6). 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-exo ipso 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 delta-lactams with a range of catalysts based upon ligands 2 and 26. The stereoselectivity of cyclisation to give gamma lactams could be somewhat influenced by using chiral enantiopure copper complexes 28-30 suggesting that the reactions may involve metal-complexed radicals.