Synthesis and characterization of bis(4-amino-2-bromo-6-methoxy)azobenzene derivatives

• David Martínez-López,
• Amirhossein Babalhavaeji,
• Diego Sampedro and
• G. Andrew Woolley

Beilstein J. Org. Chem. 2019, 15, 3000–3008, doi:10.3762/bjoc.15.296

• )-(E)-bis(1λ4-piperazine-1-carboxylate) (10): (E)-1,2-Bis(4-chloro-2-methoxyphenyl)diazene (8, 100 mg, 0.32 mmol) was dissolved in toluene in a pressure tube. Then, 1-Boc-piperazine (180 mg, 0.96 mmol), tris(dibenzylideneacetone)dipalladium(0) (29.3 mg, 0.032 mmol), RuPhos (29.8 mg, 0.064 mmol), and

• (3-bromo-5-methoxy-4,1-phenylene)-(E)-bis(1λ4-piperazine-1-carboxylate) (11): Di-tert-butyl 4,4'-(diazene-1,2-diyl)bis(3-methoxy-4,1-phenylene)-(E)-bis(1λ4-piperazine-1-carboxylate) (10, 30 mg, 0.04 mmol) was dissolved in DCM, palladium acetate (1 mg, 0.004 mmol) was added, and the resulting mixture

• ]+ calcd for C32H45Br2N6O6, 767.1767; found, 767.1762. (E)-1,2-Bis(2-bromo-6-methoxy-4-(piperazin-1-yl)phenyl)diazene (5): Di-tert-butyl 4,4'-(diazene-1,2-diyl)bis(3-bromo-5-methoxy-4,1-phenylene)-(E)-bis(1λ4-piperazine-1-carboxylate) (11, 15 mg, 0.02 mmol) was dissolved in 5 mL of DCM, and 0.25 mL of TFA

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• ]. We initially introduced the piperazine unit in a quantitative yield with unprotected piperazine (not shown) [37][38]. However, purification and isolation were problematic and we found it more convenient to use Boc-piperazine (70% yield) to obtain 11. Hydrolysis of the ethyl ester (96%) with LiOH and

• mechanism. a: Rh2(esp)2 (1 mol %), CH2Cl2, rt, Cs2CO3, 50–52%. b: EtOH, reflux, 24 h, 65%. Synthesis of norfloxacin. a: Cl-EDA (1.3 equiv), Rh2(esp)2 (1 mol %), toluene, rt, Cs2CO3, 75%. b: EtOH, reflux, 24 h, 90%. c: EtI, K2CO3, DMF, 90 °C, 24 h, 85%. d: Boc-piperazine, K2CO3, CH3CN, reflux, 3 d, 70%. e

Reversible end-to-end assembly of selectively functionalized gold nanorods by light-responsive arylazopyrazole–cyclodextrin interaction

• Maximilian Niehues,
• Patricia Tegeder and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2019, 15, 1407–1415, doi:10.3762/bjoc.15.140

• aggregation of isotropic nanoparticles, the 1,4-bis(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)piperazine-based AAP linker molecule (dAAP) has been successfully applied before and it was synthesized as described in detail in the literature [38]. This divalent linker molecule can form a light-responsive 1:2

Complexation of a guanidinium-modified calixarene with diverse dyes and investigation of the corresponding photophysical response

• Yu-Ying Wang,
• Yong Kong,
• Zhe Zheng,
• Wen-Chao Geng,
• Zi-Yi Zhao,
• Hongwei Sun and
• Dong-Sheng Guo

Beilstein J. Org. Chem. 2019, 15, 1394–1406, doi:10.3762/bjoc.15.139

• Co., Ltd (Shanghai, China), GC5A [26], P-TPE [73] and TPS [74] were prepared according to the previous literature procedures. Samples The HEPES buffer solution of pH 7.4 was prepared by dissolving 2.38 g of 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) in approximate 900 mL double

An efficient and concise access to 2-amino-4H-benzothiopyran-4-one derivatives

• Peng Li,
• Yongqi Wu,
• Tingting Zhang,
• Chen Ma,
• Ziyun Lin,
• Gang Li and
• Haihong Huang

Beilstein J. Org. Chem. 2019, 15, 703–709, doi:10.3762/bjoc.15.65

• strong nucleophilicity of piperazine and morpholine, the substrates with electron-donating/withdrawing and halogen groups smoothly delivered the N-substituted 2-aminobenzothiopyranones 4j–o and 4t,u in good to excellent yields. Specifically, the substrates containing a strong electron-withdrawing group

Regioselective addition of Grignard reagents to N-acylpyrazinium salts: synthesis of substituted 1,2-dihydropyrazines and Δ⁵-2-oxopiperazines

• Valentine R. St. Hilaire,
• William E. Hopkins,
• Yenteeo S. Miller,
• Srinivasa R. Dandepally and
• Alfred L. Williams

Beilstein J. Org. Chem. 2019, 15, 72–78, doi:10.3762/bjoc.15.8

• ; Introduction Pyrazine and piperazine ring systems are key structural elements in a large number of biologically active molecules [1][2][3][4][5][6]. Compounds containing these scaffolds were shown to behave as anticancer agents [2][3][4][5], sodium channel blockers [5], and also display antiviral activity [7

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• ethanol to complete the reduction and the amino ester 18 was isolated in a 72% yield. In order to illustrate the synthetic potential of the isoxazoline 16 as an already protected amino acid moiety, we prepared the piperazine-2,5-diones 23a,b in four steps. This was achieved by the hydrolysis of the ester

• cleaved using palladium and ammonium formate to give the corresponding oximes which were immediately reduced into amines 22a,b, using zinc and hydrochloric acid, and a thermal cyclization of these crude products gave the piperazine-2,5-diones 23a,b in, respectively, 31 and 40% overall yield from compound

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N³-aryl derivatives with electron-withdrawing groups

• Nadia Gruber,
• Jimena E. Díaz and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2018, 14, 2510–2519, doi:10.3762/bjoc.14.227

• require in most cases either a large excess of the nucleophile [75][76][77] or Boc protection [78][79] in order to obtain the monoarylated product in acceptable yields. There are some reports on selective SNAr reactions of piperazine [80] but, to the best of our knowledge, uncatalyzed selective N

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• block A [1,3,5-tris(piperazinomethyl)benzene] consisted of the amination of 1,3,5-tris(bromomethyl)benzene with commercially available N-Boc-piperazine followed by deprotection, and was achieved according to the literature [39] (97% overall yield in our hands). Similarly, 2,4,6-tris[(4-hydroxy

• (in B) and rigid 1,4-phenylene with adjustable alkoxy-spacers (n = 1, 3, in C1 and C3, respectively). G-1 chloro- and piperazine-dendrons, D-Cl and D-N

  NH, as well as central building blocks B, C1 and C3, had s-triazine rings linked by C(s-triazine)–N(exocyclic) partial double bonds, which exist due

• installation of the piperazine linkers on 2a (Table 1, entry 3) and on D-Cl (Table 1, entry 5) was ensured by the use of a 300% molar excess of this inexpensive reagent. We note the long-reaction time and large temperature domains (Table 1) required in order to obtain the quantitative results shown in Scheme 2

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• Hoechst 33258. These conjugates are fluorescent dimeric bisbenzimidazoles [(DB)n and (DBP)n] tethered by oligomethylene linkers of varied lengths with or without a central 1,4-piperazine residue [117]. The low solubility of (DB)n in aqueous solution due to aggregation has forced the authors to introduce a

• 1,4-piperazine residue in the oligomethylene linkers (DBP)n, making them tetracations instead of dications for (DB)n at neutral pH. By the virtue of their higher solubility in aqueous media, (DBP)n could easily penetrate cell and nuclear membranes of living cells and inhibit in vitro eukaryotic DNA

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• exhibited enhanced membrane permeability compared with the pure API [85]. The preparation of co-crystals of 5FU with other API’s (imatinib [86] and piperazine [87]) using LAG has also been reported. Solid dispersions of acyclovir (20%) in neutral carriers (chitosan, hydroxypropylmethyl cellulose K100M® or

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• chelating mechanism. Hughes and co-workers synthesised and evaluated bivalent 1,2,3 triazole-linked galactopyranosides 14 and 15 as shown in Figure 7 [48]. They used a piperazine core as central divalent core on to which the galactose units were attached via flexible linkers. They found that these compounds

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• bicyclic piperazine (quinoxaline) derivative 73 in 61% yield [68] (Scheme 23). The analogous reaction with [(S)-pyrrolidin-2-yl]methylamine ((S)-prolinamine) with E-1a–c occurred smoothly in CH2Cl2 at room temperature yielding optically active (4-oxohexahydropyrrolo[1,2-a]pyrazin-3-ylidene)-2-cyanoacetates

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• ), piperazine (1i,j) or tetramethyldisiloxane (1k–o) fragments, was also feasible. Interestingly, the use of N1-(2-aminoethyl)ethane-1,2-diamine as the starting material was also possible, without interference from the secondary amino group in spite of its nucleophilicity, to give compound 1h. This kind of

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• to 98% yield per coupling cycle. Evidently the lack of amide hydrogens on the support is essential for the desired solubility properties, since replacement of the piperazine fragment within the linker structure with ethylene diamine 8 gave considerably less satisfactory results. When the succinyl

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• over 250 h. The reaction mixture is further mixed with HCl in MeOH/AcOEt and subjected to acid-catalyzed cyclization in a 0.3 mL coiled reactor at 140 °C (inductive heating, 800 kHz). This resulted in 88% overall yield. The isolated product is then mixed with piperazine and passed through the PEEK

• on the entire system. The process stream can be mixed with piperazine (in MeOH/NMP) and subjected to evaporation to remove ethyl acetate solvent. The outlet flow rate of the evaporator can be controlled by maintaining the liquid level inside the evaporator. The process stream can further be passed

• through the membrane separator. The outlet pressure of the aqueous stream was maintained at 2 psi pressure resulting in a perfect separation. The aryl chloride is further reacted with piperazine (1.5 equiv) to obtain 1-(diphenylmethyl)piperazine in 92% yield. The optimum conditions were 150 °C, 45 min

Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

• Ramana Sreenivasa Rao and
• Chinnasamy Ramaraj Ramanathan

Beilstein J. Org. Chem. 2017, 13, 428–440, doi:10.3762/bjoc.13.46

• Ramana Sreenivasa Rao Chinnasamy Ramaraj Ramanathan Department of Chemistry, Pondicherry University, Puducherry – 605 014, India 10.3762/bjoc.13.46 Abstract An efficient and alternative synthetic approach has been developed to prepare various N-(arylethyl)piperazine-2,6-diones from 4

• -benzenesulfonyliminodiacetic acid and primary amines using carbonyldiimidazole in the presence of a catalytic amount of DMAP at ambient temperature. Piperazine-2,6-diones are successfully transformed to pharmaceutically useful pyridopyrazines or pyrazinoisoquinolines and ene-diamides via an imide carbonyl group activation

• strategy using a Brønsted acid. Subsequent dehydrosulfonylation reactions of the ene-diamides, in a one pot manner, smoothly transformed them to substituted pyrazinones. A concise synthesis of praziquantel (1) has also been achieved through this method. Keywords: Brønsted acid; piperazine-2,6-diones

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• CO2 (entries 4–6).a Cyclisation and N-alkylation of 1 with different alcohols.a Reactions of ethanolamine.a Showing the effect of conditions on the reaction of diethanolamine 12 to form carbamate 13 and piperazine 14.a Supporting Information Supporting Information File 62: Experimental data

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• Novel, functionalized piperazine derivatives were successfully synthesized and fully characterized by 1H/13C/19F NMR, MS, elemental analysis and lipophilicity. All piperazine compounds occur as conformers resulting from the partial amide double bond. Furthermore, a second conformational shape was

• observed for all nitro derivatives due to the limited change of the piperazine chair conformation. Therefore, two coalescence points were determined and their resulting activation energy barriers were calculated using 1H NMR. To support this result, single crystals of 1-(4-nitrobenzoyl)piperazine (3a

• , monoclinic, space group C2/c, a = 24.587(2), b = 7.0726(6), c = 14.171(1) Å, β = 119.257(8)°, V = 2149.9(4) Å3, Z = 4, Dobs = 1.454 g/cm3) and the alkyne derivative 4-(but-3-yn-1-yl)-1-(4-fluorobenzoyl)piperazine (4b, monoclinic, space group P21/n, a = 10.5982(2), b = 8.4705(1), c = 14.8929(3) Å, β = 97.430

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• Zhishi Ye Kristen E. Gettys Mingji Dai Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States 10.3762/bjoc.12.70 Abstract Piperazine ranks within the top three most utilized N-heterocyclic moieties in FDA-approved small-molecule

• functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C–H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines) were applied to piperazine substrates. Keywords

• : α-lithiation; C–H functionalization; heterocycle; photoredox catalysis; piperazine; Introduction Piperazine is one of the most important saturated N-heterocycles frequently found in life-saving small-molecule pharmaceuticals [1]. In a recent statistical study done by Njardarson and co-workers

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• -workers disclosed the first enantioselective reaction of α-cyanoketones 118 to α,β-unsaturated trifluoromethyl ketones 119, utilizing a novel organocatalyst that they developed containing a piperazine moiety (S)-120 (Scheme 38) [58]. The reaction proceeded through a Michael addition to the unsaturated

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• recovered methyl ester of 9 (60% ee), although high yields were observed (Table 3, entry 1). Then, in another attempt, the malonic acid 10 was subjected to the reaction with carbonyldiimidazole (CDI) under different conditions but also in combination with a piperazine. This method has been reported for a

• efficiently obtained by condensation of the chiral acid (S)-9 with the commercially available piperazine 16. Since most of the bioactive isoindolinones have a heteroaromatic group on the lactam, we focused on the CuI arylation of amides developed by Buchwald [40], previously applied by us to racemic

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Viktoriia V. Pakalnis,
• Roman O. Iakovenko and
• Dmitry S. Yufit

Beilstein J. Org. Chem. 2014, 10, 784–793, doi:10.3762/bjoc.10.74

• give monoadduct 12a. Interaction of the latter with ketene 6a leads to unsymmetrical cis-isomer 4a' with the piperazine ring in a chair conformation. The isomer 4a' transforms through a low barrier to a much more stable isomer 4a of C2 symmetry with the piperazine ring in a boat conformation (see

• Supporting Information File 1). No intermediate structure was located on the way to the most stable conformation of trans-isomer 5a with the piperazine ring in a boat conformation. The free energies of the highest transition states on the pathways from 12a to cis-isomer 4a and trans-isomer 5a are practically