- A short and efficient synthesis of N-aryl- and N-heteroaryl-N′- (arylalkyl)piperazines
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A new synthesis of N-aryl- and N-heteroaryl-N′-(arylalkyl) piperazines using palladium-catalyzed amination of aryl bromides and heteroaryl chlorides with mono N-benzyl- or N-(arylethyl)piperazines is reported. Most coupling processes proceed in high yield and good selectivity using either diadamantyl-n-butylphosphine (1), 2-(dicyclohexylphosphino)-2′-(N,N- dimethylamino)biphenyl (2), or 2-(di-tert-butylphosphino)biphenyl (3) as ligand. Applying an automated parallel synthesizer the preparation of a small library of potentially bioactive compounds is easily achieved.
- Michalik, Dirk,Kumar, Kamal,Zapf, Alexander,Tillack, Annegret,Arlt, Michael,Heinrich, Timo,Beller, Matthias
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- Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions
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By using cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.
- Chamorro-Arenas, Delfino,Osorio-Nieto, Urbano,Quintero, Leticia,Hernández-García, Luís,Sartillo-Piscil, Fernando
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p. 15333 - 15346
(2019/01/03)
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- 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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- Ruthenium catalyzed β-C(sp3)-H functionalization on the 'privileged' piperazine nucleus
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β-C(sp3)-H functionalization on the 'privileged' piperazine nucleus has been disclosed using ruthenium catalysis. The ruthenium catalyzed synthesis of a variety of piperazine fused indoles from ortho-piperazinyl (hetero)aryl aldehydes is presented. This transformation takes place via the dehydrogenation of piperazine followed by an intramolecular nucleophilic addition of the transient enamine moiety onto the carbonyl group and aromatization cascade.
- Murugesh,Bruneau, Christian,Achard, Mathieu,Sahoo, Apurba Ranjan,Sharma, Gangavaram V. M.,Suresh, Surisetti
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supporting information
p. 10448 - 10451
(2017/09/25)
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- A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets
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We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 μL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD.
- Hwang, Ye-Jin,Coley, Connor W.,Abolhasani, Milad,Marzinzik, Andreas L.,Koch, Guido,Spanka, Carsten,Lehmann, Hansjoerg,Jensen, Klavs F.
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p. 6649 - 6652
(2017/07/10)
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- Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents
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The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBPn) and triazole phosphates (Si-OTPn) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBPn and Si-OTPn, can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity.
- Maity, Pradip K.,Faisal, Saqib,Rolfe, Alan,Stoianova, Diana,Hanson, Paul R.
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p. 9942 - 9950
(2015/11/03)
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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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- Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties
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We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl) -4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [ 3H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (Ki = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (KB = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (KB = 0.017 nM).
- Romeiro, Luiz A.S.,Da Silva Ferreira, Marcos,Da Silva, Leandro L.,Castro, Helena C.,Miranda, Ana L.P.,Silva, Cláudia L.M.,No?l, Franois,Nascimento, Jéssica B.,Araújo, Claudia V.,Tibiri?á, Eduardo,Barreiro, Eliezer J.,Fraga, Carlos A.M.
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experimental part
p. 3000 - 3012
(2011/07/08)
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- ROMP-derived oligomeric phosphates for application in facile benzylation
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The development of new ROMP-based oligomeric benzyl phosphates (OBP n) is reported for use as soluble, stable benzylating reagents. These oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot process, affording bench-stable, pure white, free-flowing solids on multigram scale. Utilization in benzylation reactions with a variety of nucleophiles is reported.
- Long, Toby R.,Maity, Pradip K.,Samarakoon, Thiwanka B.,Hanson, Paul R.
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supporting information; experimental part
p. 2904 - 2907
(2010/09/30)
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- An expedient three-component synthesis of tertiary benzylamines
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A Mannich-like zinc-mediated three-component reaction of aromatic halides, amines, and paraformaldehyde is described. This procedure, which involves the in situ formation of arylzinc reagents, allows the straightforward synthesis of a range of functionalized tertiary benzylamines. Georg Thieme Verlag Stuttgart.
- Le Gall, Erwan,Decompte, Alexandre,Martens, Thierry,Troupel, Michel
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experimental part
p. 249 - 254
(2010/04/05)
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- Oligomeric benzylsulfonium salts: Facile benzylation via high-load ROMP reagents
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(Chemical Equation Presented) The development of high-load, oligomeric benzylsulfonium salts, generated via ring-opening metathesis polymerization, and their utility in facile benzylations of various nucleophiles is reported. These oligomeric sulfonium salts exist as free-flowing powders and are stable at room temperature. After the benzylation event, purification is attained via simple dry load/filtration, followed by solvent removal to deliver products in excellent yield and purity.
- Zhang, Mianji,Flynn, Daniel L.,Hanson, Paul R.
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p. 3194 - 3198
(2008/02/04)
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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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- Development of high-load, soluble oligomeric sulfonate esters via ROM polymerization: Application to the benzylation of amines
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The development of high-load, soluble oligomeric sulfonate esters, generated via ROM polymerization, and their utility in the facile benzylation of an array of amines is reported. These polymeric sulfonate esters exist as free-flowing powders, are stable
- Zhang, Mianji,Moore, Joel D.,Flynn, Daniel L.,Hanson, Paul R.
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p. 2657 - 2660
(2007/10/03)
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- INHIBITORS OF FUNGAL INVASION
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This invention relates to various anti-fungall agents including agents that are inhibitors of fungal invasion.
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Drawing sheet 10
(2010/02/09)
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- Microwave assisted, highly efficient solid state N- and S-alkylation
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Secondary amines and thiophenols were alkylated with alkyl and benzyl halides rapidly on alumina supported potassium carbonate under solvent-free conditions using microwaves. Equimolar amounts of the secondary amine/thiophenol and alkyl halide were used. The procedure neither required any strong base nor a PTC Aniline was also monobenzylated with benzylchloride. Separation of the products from the reactants was very simple by using a nonpolar solvent for desorption.
- Jaisinghani, Harsha G.,Khadilkar, Bhushan M.
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p. 3693 - 3698
(2007/10/03)
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- New generation dopaminergic agents. 2. Discovery of 3-OH-phenoxyethylamine and 3-OH-N1-phenylpiperazine dopaminergic templates
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Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonist as well as templates for the future design of novel dopaminergic agents.
- Mewshaw, Richard E.,Husbands, Morris,Gildersleeve, Elizabeth S.,Webb, Michael B.,Shi, Xiaojie,Mazandarani, Hossein,Cockett, Mark I.,Ochalski, Rafal,Brennan, Julie A.,Abou-Gharbia, Magid,Marquis, Karen,McGaughey, Georgia B.,Coupet, Joseph,Andree, Terrance H.
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p. 295 - 300
(2007/10/03)
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