On a Simple Hydrogen Cyanide-Based Access to Piperazin-2-ones

Abstract This report describes a scope exploration of a rarely used access to piperazin-2-ones from carbonyls, hydrogen cyanide (generated in situ from acetic acid and potassium cyanide), and ethylenediamine as well as N- or C-substituted alkyl 1,2-diamines. Our findings show that this synthesis plausibly proceeds via imines and/or imidazoline intermediates and, upon addition of hydrogen cyanide, to α,δ-diaminonitriles. Their ensuing cyclization leads to piperazin-2-imines, which then require a hydrolysis stage at high temperature, using a microwave oven, to generate the corresponding piperazin-2-ones. Although the reaction proceeds sometimes in very modest yields (ranging from 4% to 84%), its rather large scope (illustrated by 73 original examples) are described here, as well as the many commercially available starting materials offering at least a one-pot alternative to prepare original libraries of chemicals featuring a piperazin-2-one component.