Direct Synthesis of Highly Substituted Pyrroles and Dihydropyrroles Using Linear Selective Hydroacylation Reactions

Abstract

Rhodium(I) catalysts incorporating small bite-angle diphosphine ligands, such as (Cy2P)2NMe or bis(diphenylphosphino)methane (dppm), are effective at catalysing the union of aldehydes and propargylic amines to deliver the linear hydroacylation adducts in good yields and with high selectivities. In situ treatment of the hydroacylation adducts with p-TSA triggers a dehydrative cyclisation to provide the corresponding pyrroles. The use of allylic amines, in place of the propargylic substrates, delivers functionalised dihydropyrroles. The hydroacylation reactions can also be combined in a cascade process with a RhI-catalysed Suzuki-type coupling employing aryl boronic acids, providing a three-component assembly of highly substituted pyrroles. Down the line: Rhodium catalysts featuring small-bite-angle bisphosphine ligands allow the linear-selective combination of aldehydes and propargylic amines (see scheme). The resultant γ-amino-enone products are converted in situ to a diverse range of substituted pyrroles. Allylic amine substrates can also be employed, leading in these cases to dihydropyrrole products.