- 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
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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.
- Ghazanfarpour-Darjani, Majid,Barat-Seftejani, Forugh,Khalaj, Mehdi,Mousavi-Safavi, Seyed Mahmoud
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- Synthesis of N-alkyl-N′-aryl-piperazines via copper-catalyzed C-N bond formation
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An efficient copper-catalyzed tandem synthesis of N-alkyl-N′-aryl-piperazines from 1,4-diaza-bicyclo[2.2.2]octane, alkyl halides, and aryl halides in the presence of copper(I) iodide and potassium tert-butoxide in DMSO is described.
- Yavari, Issa,Bayat, Mohammad J.,Ghazanfarpour-Darjani, Majid
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p. 5595 - 5596
(2014/12/11)
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- Interaction of arylpiperazines with the dopamine receptor D2 binding site
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The docking of several 1-benzyl-4-arylpiperazines to the dopamine receptor (DAR) D2 was examined. The results demonstrated that the interaction of protonated N1 of the piperazine ring with Asp 86 (III.32) and edge-to-face interactions of the aromatic ring of the arylpiperazine part of the ligand with Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) of the receptor, represent the major stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could build one more hydrogen bond with Trp 182 (VI.48). Bulky substituents in position 4 were not tolerated due to the unfavorable sterical interaction with Phe 178 (VI.44). Substituents in position 2 and 3 were found to be sterically well tolerated. Introduction of electron attractive -NO2 group in position 3 of arylpiperazines decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity comparing to that of the phenylpiperazine 1. This can be explained in terms of favoured edge-to-face interactions in ligands with a high negative electrostatic surface potential (ESP) in the centre of aromatic residue of arylpiperazines. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands to form complexes with the DAR D2. Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) can be considered as a part of the ancillary DAR D2 pocket preserved in most G protein-coupled receptors of the A class and obviously, the arylpiperazine structural motif represents one of the privileged structures that bind to this pocket.
- Sukalovic, Vladimir,Zlatovic, Mario,Andric, Deana,Roglic, Goran,Kostic-Rajacic, Sladjana,Soskic, Vukic
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p. 145 - 152
(2007/10/03)
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