Cascade cyclization intermolecular dipolar cycloaddition by multi-component couplings—synthesis of indolizidines and pyrrolizidines

A three-component coupling reaction of a primary amine (an amino-acid or amino-ester or hydroxylamine), an alkene or alkyne dipolarophile and an aldehyde bearing a halide as a leaving group has been developed. Condensation of the amine with the aldehyde and cyclization (intramolecular N-alkylation) provides, after decarboxylation or deprotonation, a cyclic azomethine ylide (or nitrone) that undergoes intermolecular dipolar cycloaddition with the dipolarophile. This sets up, in a single step, the bicyclic indolizidine or pyrrolizidine ring system, depending on the length of the tether between the aldehyde and the halide. The reaction is successful with stabilized and non-stabilized azomethine ylides that result from using primary amino-esters or amino-acids, respectively.