Ammonium zincates as catalysts for the selective coupling of aziridines to yield piperazines

The piperazine ring is found in many drugs with central pharmacological activity.1 Aziridines, on the other hand, are common synthetic intermediates, as their pronounced geometrical strain allows them to readily perform ring opening reactions under the stimulus of an appropriate nucleophile. In our recent investigation on the catalytic activity of ammonium ferrates and zincates as active catalysts in the CO2 cycloaddition to epoxides2 and aziridines3 to yield cyclic carbonates and carbamates, respectively, we have disclosed that with the latter, symmetrical piperazines were formed as the only by-products (less than 5%) when decreasing the CO2 pressure . We report here that in the absence of CO2, ammonium zincates are suitable catalyst to promote the catalytic dimerization of aziridines to yield 2,5 cis or trans disubstituted piperazines (figure 1). We developed a convenient and straightforward protocol for the synthesis of symmetrically substituted piperazines from commonly available laboratory reagents. This method yields two different stereoisomers of the same piperazine, namely the (+/-)-form and the meso form. The two are easily separated by a simple filtration, as the meso form readily crystalizes in excellent purity at the end of the reaction. The catalysts, ammonium zincates (R4N[ZnX4], X = Cl, Br, I), can be easily and cheaply synthetized from readily available and inexpensive materials, simply by mixing two ethanolic solutions of an alkylammonium salt and a zinc halide. Their scope extends over a number of substrates, ranging from N-alkyl to less activated N-tosyl aziridines. Excellent yields and purity have been obtained by microwave heating (dielectric heating). We believe that this work represents a useful addition to an already large set of metalates catalyzed reactions.