Rapid Access to Substituted Piperazines via Ti(NMe2)4-Mediated C–C Bond-Making Reactions

Abstract

An efficient Ti(NMe2)4-mediated C–C bond-forming methodology toward substituted piperazines, the basic skeleton of several biologically active natural products, has been developed. In reactions of tridentate monoanionic ligands bearing a [−HCNCH2−] linkage with Ti(NMe2)4, unusual [3 + 3] dimerized complexes through C–C coupling of the putative titanium aza-allyl complex intermediate could be obtained. These complexes contain substituted piperazine backbones and could give rise efficiently to substituted piperazine derivatives via hydrolysis. Treatment of Ti(NMe2)4 with a series of tridentate dianionic and bidentate monoanionic ligands bearing the [−HCNCH2−] moiety only generated chelated titanium complexes from ligand exchange reactions. Mechanistic studies using DFT/M06 calculations revealed that the methylene in the [−HCNCH2−] moiety of titanium complexes bearing tridentate monoanionic ligands could be deprotonated intramolecularly by dimethylamide anion with an activation energy of about 22 kcal/mol. The resulting titanium aza-allyl complexes from this β-H abstraction step then undergo a consecutive stepwise [3 + 2] cycloaddition/ring expansion reaction facilely to form the dimerized complex. However, β-H abstractions for Ti complexes bearing tridentate dianionic and bidentate monoanionic ligands were energetically demanding, as the negative charges could not be stabilized by the adjacent groups in the possible intermediates, explaining the experimental outcomes that no C–C coupled products were formed.