Synthesis of N‐alkyl‐N′‐aryl or Alkenylpiperazines: A Copper‐Catalyzed C–N Cross‐Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO

Abstract

Unsymmetrical piperazines are key constituents of many pharmaceuticals. Given that the selective introduction of an aryl and alkyl motif onto the piperazine is not always straightforward, direct arylation and alkenylation of 1,4‐diaza‐bicyclo[2.2.2]octane would obviate the inefficiencies associated with the preparation of these target molecules. We have utilized alkyl halides, aryl or alkenyl triflates, and 1,4‐diaza‐bicyclo[2.2.2]octane for the synthesis of N‐alkyl‐N′‐aryl or alkenylpiperazines. The optimum conditions are developed using CuCl, t‐BuOLi in NMP. Alkenyl triflates requires N,N′‐dimethylethylenediamine and higher temperature to afford the desired cross‐coupled product. Substrates bearing electron‐deficient and electron‐rich groups were successfully coupled under the optimum reaction conditions.

DABCO bond cleavage for the synthesis of piperazine derivatives

“…In addition, the synthesis of unsymmetrical piperazines with the same strategy is further developed by Ghazanfarpour-Darjani and coworkers. 43 They have utilized alkyl chlorides, DABCO ring opening reaction (Scheme 30). 44 Diversely substituted pyridine N-oxides, quinolone-N-oxides, and 1,10phenanthroline 1-oxide were applied successfully in this protocol.…”

“…In addition, the synthesis of unsymmetrical piperazines with the same strategy is further developed by Ghazanfarpour-Darjani and coworkers. 43 They have utilized alkyl chlorides, aryl(heteroaryl) triflates and DABCO under optimal reaction conditions [CuCl (5 mol%), t -BuOLi (1.5 equiv. ), and NMP as solvent at 70 °C for 14 h] to provide N -alkyl- N ′-aryl (heteroaryl) piperazines 78 in 73–93% yields.…”

Factors Governing Selectivity of Dopamine Receptor Binding Compounds for D2R and D3R Subtypes

“…We have previously reported that covalently coupling a four-carbon chain linker and a moiety capable of binding a secondary binding site (SBS) (also referred to as an allosteric site) to phenyl­piperazine analogs modulates their affinity and selectivity for the D2R and D3R subtypes. Furthermore, we also found that the addition of a phenyl­thiophene moiety generates D3R vs D2R selective ligands that bind with high affinity to the D3R. − Previous studies suggested that the SBS is located in the extracellular loops (ECL) of the D3R. , In contrast, coupling the phenyl­piperazine with the linker and 4-dihydro-2­(1 H )-quinolinone causes the compounds to be D2R selective, which is not desirable for therapeutic purposes . In this manuscript, we further investigate how compounds that either lack or contain an allosteric fragment interact at the D2R and D3R subtypes using both experimental and computational approaches.…”