Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

• Richard J. Ingham,
• Claudio Battilocchio,
• Joel M. Hawkins and
• Steven V. Ley

Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56

• treatment of tuberculosis – and its reduced derivative piperazine-2-carboxamide. Keywords: automation; flow chemistry; hydration; hydrogenation; sustainable processing; Introduction Enabling synthesis technologies such as flow chemistry are becoming commonplace in modern laboratories (for recent reviews

• database for medicinal chemistry. For example, piperazine-2-carboxamide (1, Figure 2a) is an amino acid derivative with interesting biological properties [17]. At the time of writing, racemic 1 was identified as a notably expensive building block [18] and thus a good target for this transformation. We have

• pyrazine 2 to piperazine 1 (Figure 2b). Both of these steps involve flowing through heterogeneous catalysts, a metal oxide for the hydration of the nitrile and a supported precious metal for the hydrogenation of the heteroaromatic ring. Furthermore, both steps involve the addition of a volatile small

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• in e.g. beer, cacao and coffee [138][139][140]. The DKPs occur in three different isomers, in which the position of one oxo-group is different at the piperazine-ring [26]. The 2,5-diketopiperazines are most relevant due to the structural similarity with peptides (Figure 1). The DKP core shows

Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

• Jie-Ping Wan,
• Yunfang Lin,
• Kaikai Hu and
• Yunyun Liu

Beilstein J. Org. Chem. 2014, 10, 287–292, doi:10.3762/bjoc.10.25

• demonstrated that 0.5 equiv of piperazine was favorable (Table 1, entries 4–6). Reducing the amount of TMSCl led to a decrease in product yield (Table 1, entry 7). Other Lewis acid or Brønsted acids such as FeCl3 and p-TSA gave no better result for the same reaction (Table 1, entries 8 and 9). In addition, the

• 2 (0.4 mmol) and alkyl propionate 3 (0.3 mmol) piperazine (0.15 mmol), and p-tolylsulfonic acid (0.15 mmol, 0.3 mmol for the reaction of urea) were charged in a 25 mL round bottom flask equipped with a stirring bar. DMF (THF for the reaction of urea) (4 mL) and TMSCl (0.6 mmol, 0.9 mmol for the

• and removing of the solvent under reduced pressure, the residue was subjected to flash column chromatography to provide pure products. Synthesis of intermediate 6a. Into a 25 mL round bottom flask was added ethyl propiolate (0.6 mmol) and piperazine (0.3 mmol). 1.5 mL DMF was added and the mixture was

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• N-methylene groups of the amide [44]. With the exception of the piperazine derivative 5d, the observed diastereomeric ratio in the β-lactam products was approximately 6:1, favouring the diastereomer in which the bromine atom and the ring fragment are in a trans relationship (hereafter referred to as

Facile synthesis of benzothiadiazine 1,1-dioxides, a precursor of RSV inhibitors, by tandem amidation/intramolecular aza-Wittig reaction

• Krishna C. Majumdar and
• Sintu Ganai

Beilstein J. Org. Chem. 2013, 9, 503–509, doi:10.3762/bjoc.9.54

• double bonds in various heterocycles and heterocycle-containing natural products [33][34][35][36][37][38][39][40][41][42][43]. Recently, we have synthesized asymmetrically substituted piperazine-2,5-dione derivatives using the intramolecular aza-Wittig reaction [44]. In continuation of our earlier work

Synthesis of meso-substituted dihydro-1,3-oxazinoporphyrins

• Satyasheel Sharma and
• Mahendra Nath

Beilstein J. Org. Chem. 2013, 9, 496–502, doi:10.3762/bjoc.9.53

• [25], pyrrolidinone [26], pyrrolidine [27] and piperazine [28], to the porphyrin periphery. In addition, many porphyrin dimers and trimers have displayed significant biological efficacy [29] and some of these are used as photosensitizers in PDT applications for the treatment of various types of

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• potential for lysosomotropic behavior [31][32]. We sought to address the question of lysosomotropism by preparing analogues of 1 in which the basic piperazine substituent at “P3” (which binds the S3 subsite of cruzain) was replaced with nonbasic or weakly basic heterocycles. In our initial structure

A bisazobenzene crosslinker that isomerizes with visible light

• Subhas Samanta,
• Harris I. Qureshi and
• G. Andrew Woolley

Beilstein J. Org. Chem. 2012, 8, 2184–2190, doi:10.3762/bjoc.8.246

• of a new crosslinker in which a central piperazine unit links two azobenzene chromophores. Molecular modeling indicates that this crosslinker can undergo a large change in end-to-end distance upon trans,trans to cis,cis isomerization. Photochemical characterization indicates that it does isomerize

• -lifetimes may be longer when the crosslinker is attached to a biomolecule, it appears the para-piperazine unit may be best suited for applications where rapid thermal relaxation is required. Keywords: azobenzene; molecular switches; switch; photo-control; visible; Introduction Azobenzene derivatives have

• toxic stimulus [25][26]. In an attempt to red-shift the switching wavelength while maintaining a large end-to-end distance change upon photoisomerization, we designed compound 2 (Scheme 1). The central piperazine unit in this structure was expected to disconnect the π-delocalization between the two azo

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

• Rajendra Surasani,
• Dipak Kalita,
• A. V. Dhanunjaya Rao and
• K. B. Chandrasekhar

Beilstein J. Org. Chem. 2012, 8, 2004–2018, doi:10.3762/bjoc.8.227

• -protected piperazine (Table 4, entry 8). The reaction works equally well for aliphatic primary amine too (Table 4, entry 7) resulting in 90% isolated yield. There was a feeble change in yield by varying the substitution on the 7-azaindole nitrogen (N1) from a methyl to an ethyl group (Table 4, entries 6–8

Engineering of indole-based tethered biheterocyclic alkaloid meridianin into β-carboline-derived tetracyclic polyheterocycles via amino functionalization/6-endo cationic π-cyclization

• Piyush K. Agarwal,
• Meena D. Dathi,
• Mohammad Saifuddin and
• Bijoy Kundu

Beilstein J. Org. Chem. 2012, 8, 1901–1908, doi:10.3762/bjoc.8.220

• nortopsentins [21][22][23]), dihydroimidazole (discodermindole [24]), oxadiazine (alboinon [25]), piperazine (dragmacidon [26]), maleimide (didemidines [25]), and pyrimidine (meridianins) [27][28][29]. Among these, meridianins (Figure 1), the tethered biheterocycles isolated from the south Atlantic tunicate

Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

• Torsten Dittrich,
• Nils Hanekop,
• Nacera Infed,
• Lutz Schmitt and
• Manfred Braun

Beilstein J. Org. Chem. 2012, 8, 1700–1704, doi:10.3762/bjoc.8.193

• multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has

• crucial for inhibitory activity on P-glycoprotein [14][15][16][17][18], our strategy was based on modification or replacement of the dibenzosuberyl and the piperazine moieties, whereas the above-mentioned “southern part” of zosuquidar (1a) was planned to be maintained, including the absolute configuration

• of the stereogenic carbinol center. Thus, we replaced the piperazine motif in 1 by a piperidine ring carrying either nitrogen or oxygen as a hetero substituent(s) in the 4-position. Therefore, an initial series of 4-aminopiperidines 2a–4a and, in a second approach, new spirocyclic acetals 5a–12a as

Parallel solid-phase synthesis of diaryltriazoles

• Matthias Wrobel,
• Jeffrey Aubé and
• Burkhard König

Beilstein J. Org. Chem. 2012, 8, 1027–1036, doi:10.3762/bjoc.8.115

• , 4.25; N, 23.75. Terphenyl scaffold 1 [13][14]; oxazole-pyridazine-piperazine 2 [14][15] and aryl-triazoles 3 and 4 [15][16] as α-helix mimetics. Synthesis of azido-functionalized resins 7 and 9. Copper-catalyzed [2 + 3] cycloadditions of resin-bound azide 7 with five terminal alkynes. Copper-catalyzed

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• , piperazine and homo-piperazine, were also investigated. Accordingly, a small series of Sant-75 analogues 18a–j were synthesized in a parallel fashion from the corresponding intermediates 19a–j. For intermediates 19a–j, different coupling reactions were required to achieve their synthesis, depending on the

Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model

• Hanno Sell,
• Anika Gehl,
• Frank D. Sönnichsen and
• Rainer Herges

Beilstein J. Org. Chem. 2012, 8, 81–89, doi:10.3762/bjoc.8.8

• titrations three different buffer stock solutions were used: pH 7.6: HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid), pH 8.5: EPPS (4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid) and pH 9.5: CHES (2-(cyclohexylamino)ethanesulfonic acid). The stock solutions had a total buffer concentration

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• studies this fused heterocycle was found to be more metabolically stable compared to earlier leads that contained a simple piperazine ring. Furthermore, the triazolopiperazine is not only involved in a tight H-bond network within the active site of DPP-IV, but also in π-stacking with the aromatic ring of

• 283 was then subjected to cyclodehydration using phosphoryl chloride to give a chloromethyl oxadiazole derivative 284. In a cleverly staged transformation, this compound was treated with diaminoethane to yield the piperazine ring 285, which, on heating under reflux in methanol, undergoes a further

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• synthesis of biological active molecules A typical example for the application of palladium-catalysed N-aryl bond formation is the synthesis of highly selective D3 receptor ligands 4. Piperazine (1) and a substituted aryl bromide 2 (Scheme 1) are coupled in the initial step of the synthesis. The electron

• structure–activity relationship [49]. Federsel et al. used a piperazine derivative 6 and an aryl halide 5 for the preparation of a CNS-active substituted chiral aminotetralin 7 (Scheme 2) [50]. The 5-HT1B receptor antagonist 8 was developed for the treatment of certain neuronal disorders. Different

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

Comparison of zwitterionic N-alkylaminomethanesulfonic acids to related compounds in the Good buffer series

• Robert D. Long,
• Newton P. Hilliard Jr,
• Suneel A. Chhatre,
• Tatiana V. Timofeeva,
• Andrey A. Yakovenko,
• Daniel K. Dei and
• Enoch A. Mensah

Beilstein J. Org. Chem. 2010, 6, No. 31, doi:10.3762/bjoc.6.31

• methodology to produce other compounds that are the α-aminosulfonic acid analogs of other commonly used Good buffers including N-(2-hydroxyethyl)piperazine-N′-methanesulfonic acid [HEPMS] (2), piperazine-N,N′-bis(methanesulfonic acid) [PBMS] (3), and cyclohexylaminomethanesulfonic acid [CAMS] (4). Our initial

• sulfonic acid and amino group is if the zwitterion is formed by protonation at the piperazine nitrogen that is bonded to the hydroxyethyl functional group. This nitrogen’s basicity would be expected to be only slightly impacted by structural modifications of the alkylsulfonic acid group at the other

• nitrogen. This hypothesis is supported by the crystal structure of HEPMS 2 as a zwitterion shown in Figure 4. The crystal structure of 2 is consistent with the one previously reported for HEPES [11]. Both have piperazine rings in the chair conformation, with extended conformation for the side chains. Both

Continuous flow enantioselective arylation of aldehydes with ArZnEt using triarylboroxins as the ultimate source of aryl groups

• Julien Rolland,
• Xacobe C. Cambeiro,
• Carles Rodríguez-Escrich and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2009, 5, No. 56, doi:10.3762/bjoc.5.56

• stereospecific ring-opening with piperazine, and the resulting diamino alcohol 3 is subsequently supported onto a slightly cross-linked (1% DVB) Merrifield resin by direct treatment at room temperature in DMF in the presence of cesium carbonate (Scheme 3). Evaluation of resin 2 under batch conditions Prior to

Iridium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes with secondary amine nucleophiles

• Dingqiao Yang,
• Ping Hu,
• Yuhua Long,
• Yujuan Wu,
• Heping Zeng,
• Hui Wang and
• Xiongjun Zuo

Beilstein J. Org. Chem. 2009, 5, No. 53, doi:10.3762/bjoc.5.53

• catalyst. The trans-1,2-dihydronaphthalenol product 2 is subsequently released and the iridium monomer B is regenerated. Conclusion In summary, we have explored the iridium-catalyzed ARO reaction of oxabicyclic alkenes with N-alkylated anilines or N-substituted piperazine nucleophiles; the reactions gave

Hydrogen bonding patterns in the cocrystals of 5-nitrouracil with several donor and acceptor molecules

• Reji Thomas,
• R. Srinivasa Gopalan,
• G. U. Kulkarni and
• C. N. R. Rao

Beilstein J. Org. Chem. 2005, 1, No. 15, doi:10.1186/1860-5397-1-15

• , pyridine, DMSO, formamide and ethanol as well as with piperazine, N, N'-dimethylpiperazine, 3-aminopyridine and diazabicyclo [2.2.2]octane obtained by deliberate inclusion, have been examined by X-ray crystallography. The tape structure found in the parent centric form of nitrouracil is retained with some

• modifications in the cocrystals with dioxane, piperazine, diazabicyclo [2.2.2]octane, N,N'-dimethylpiperazine, pyridine and DMSO, with the guest molecules forming alternate tapes. In cocrystals involving formamide, ethanol and 3-aminopyridine, the molecular tapes exhibit mixed compositions. The observed bonding

• cocrystals of I with other electron donor compounds such as piperazine, N,N'-dimethylpiperazine, 3-aminopyridine and diazabicyclo [2.2.2]octane. Crystallographic structures of the cocrystals so obtained have revealed interesting changes in the hydrogen bonding pattern of I in the presence of other molecules