Ultrasound-assisted Strecker synthesis of novel 2-(hetero)aryl-2-(arylamino)acetonitrile derivatives

• Emese Gal,
• Luiza Gaina,
• Hermina Petkes,
• Alexandra Pop,
• Castelia Cristea,
• Gabriel Barta,
• Dan Cristian Vodnar and
• Luminiţa Silaghi-Dumitrescu

Beilstein J. Org. Chem. 2020, 16, 2929–2936, doi:10.3762/bjoc.16.242

• trimethylsilyl cyanide (TMSCN) in poly(ethylene glycol) (PEG) solution. The advantages of the sonochemical versus the conventional α-(arylamino)acetonitrile synthesis are the significantly shorter reaction time (30 min instead of 72 hours), the higher purity and the easier separation of the product that

• , ferrocene or benzene units was screened by the Salmonella mutagenicity assay (Ames test) [28] using S. typhimurium TA98 and TA100 strains. Results and Discussions Ultrasound-assisted synthesis The Strecker reaction between (hetero)aromatic aldimines and TMSCN in poly(ethylene glycol) (PEG)–water medium [18

• TMSCN (1 equiv) to a solution containing the aldimine (1 equiv) dissolved in PEG (5 mL) and water (1 mL). After completion of the reaction, the product was collected by filtration directly from the reaction mixture, or after being poured into water. The crystalline product was dried and if necessary

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol

• María C. Mollo,
• Natalia B. Kilimciler,
• Juan A. Bisceglia and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2020, 16, 32–38, doi:10.3762/bjoc.16.5

• reactions in either case. The synthesis of 2-phenyl-4,5,6,7-tetrahydro-1,3-thiazepine by cyclodehydration of N-(4-hydroxybutyl)thiobenzamide was attempted with different condensing agents: PPA (100 °C, 15 h), Burgess (25 °C, 48 h) and PEG-Burgess (80 °C, 2 h) reagents, and under Mitsunobu conditions. In the

• first case, the 1H NMR spectrum of the resulting product contained no signals in the aromatic region [31]. The Burgess reagent led to 58% of the desired product, while the modified PEG-Burgess reagent yielded a mixture of the thiazepine (17%) and the isomeric N-thiobenzoylpyrrolidine (40%). The use of

• -thiobenzoylaminobutanol with PEG-linked Burgess reagent and under Mitsunobu conditions led to significant amounts of N-thiobenzoylpyrrolidine [32]. In fact, this kinetically favoured competitive reaction also occurs in the closely related cyclization of N-benzoylaminobutanol with PPSE, which leads exclusively to N

Targeted photoswitchable imaging of intracellular glutathione by a photochromic glycosheet sensor

• Xianzhi Chai,
• Hai-Hao Han,
• Yi Zang,
• Jia Li,
• Xiao-Peng He,
• Junji Zhang and
• He Tian

Beilstein J. Org. Chem. 2019, 15, 2380–2389, doi:10.3762/bjoc.15.230

• control reporter 8o with a PEG chain instead of the galactoside targeting group was also prepared. The detailed synthetic procedures and characterizations are given in Supporting Information File 1. Photochromic performances of Glyco-DTE The photoswitching performances of Glyco-DTE (1 × 10−5 mol/L) were

Fluorescent phosphorus dendrimers excited by two photons: synthesis, two-photon absorption properties and biological uses

• Anne-Marie Caminade,
• Artem Zibarov,
• Eduardo Cueto Diaz,
• Aurélien Hameau,
• Maxime Klausen,
• Kathleen Moineau-Chane Ching,
• Jean-Pierre Majoral,
• Jean-Baptiste Verlhac,
• Olivier Mongin and
• Mireille Blanchard-Desce

Beilstein J. Org. Chem. 2019, 15, 2287–2303, doi:10.3762/bjoc.15.221

• one case, phenol PEG (poly(ethylene glycol) was grafted together with pyridine imine phenol, affording dendrimers stochastically functionalized on the surface, but all having precisely 12 fluorophores in the internal structure [59]. Another way to induce solubility in water consists in having

• the synthesis was carried out up to the second generation, then 24 phenol-PEG were grafted. In the second case, the synthesis was carried out up to the third generation, which was functionalized with 48 ammonium groups (Figure 6). Photo-physical studies of both compounds indicated that the

• fluorophores are more protected by the PEG groups of the second generation G2 than by the ammonium groups of the third generation G3 as indicated by the quantum yields Φf = 0.24 (G3 ammonium) and 0.39 (G2 PEG). However, the TPA cross-section measurements gave σ2max = 13,600 GM for G3 ammonium, and 8,400 GM for

An overview of the cycloaddition chemistry of fulvenes and emerging applications

• Ellen Swan,
• Kirsten Platts and
• Anton Blencowe

Beilstein J. Org. Chem. 2019, 15, 2113–2132, doi:10.3762/bjoc.15.209

• functionalised fulvene as the polydiene. Initially, a fulvene derivative (4-(cyclopenta-2,4-dien-1-ylidene)pentanoic acid) was conjugated to dextran, and employed in DAC at 37 °C with a dichloromaleic acid-modified PEG derivative (Scheme 20) [191]. The formed hydrogels exhibited self-healing at physiological

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

A heteroditopic macrocycle as organocatalytic nanoreactor for pyrroloacridinone synthesis in water

• Piyali Sarkar,
• Sayan Sarkar and
• Pradyut Ghosh

Beilstein J. Org. Chem. 2019, 15, 1505–1514, doi:10.3762/bjoc.15.152

• the product was detected when the reaction was carried out in ethanol/water 1:1 (Table 1, entry 12). Even when repeating the reaction in the presence of the phase-transfer catalyst, poly(ethylene glycol) (PEG) no mentionable yield of product was observed (Table 1, entries 13 and 14). The subsequent

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• conjugation at the N-terminus required microwave irradiation due to the bulkier character of the amino component. Besides steroids, the method worked well with varied boronic acids, including those bearing fluorescent labels, lipids and PEG chains, thus providing a new class of biomolecular conjugates showing

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• (33) is replaced by bromoisobenzofuranone 61, also leading to isoindoloquinazoline derivatives 57 (Scheme 18) [99]. After optimization of the reaction conditions, a 4:1 combination of water and PEG-400 was chosen as the best solvent and an array of nineteen isoindoloquinazolinones 57 with yields

Catalyst-free assembly of giant tris(heteroaryl)methanes: synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts

• Rodrigo Abonia,
• Luisa F. Gutiérrez,
• Braulio Insuasty,
• Jairo Quiroga,
• Kenneth K. Laali,
• Chunqing Zhao,
• Gabriela L. Borosky,
• Samantha M. Horwitz and
• Scott D. Bunge

Beilstein J. Org. Chem. 2019, 15, 642–654, doi:10.3762/bjoc.15.60

• ]. Furthermore, it is highly desirable to perform these reactions in environmentally friendly solvents such as water, ethanol, and PEG [6][7]. Motifs bearing triarylmethane (Ar3CH) [8][9][10] and their heterocyclic variants (Het-Ar)3CH [8][9][10][11][12], constitute an integral part of a number of bioactive

Cyclopropene derivatives of aminosugars for metabolic glycoengineering

• Jessica Hassenrück and
• Valentin Wittmann

Beilstein J. Org. Chem. 2019, 15, 584–601, doi:10.3762/bjoc.15.54

• allowed the determination of rate constants in aqueous solution. As reported for ManNCyoc, an excess of ManNCyc and ManNCp, respectively, was reacted with water-soluble tetrazine Tz-PEG-OH in acetate buffer (pH 4.7, Figure 2A). The decrease of absorption of Tz-PEG-OH at λmax = 522 nm was measured and

• peracetylation step. Stock solutions of Tz-PEG-OH and sugar were prepared in acetate buffer (pH 4.8) and mixed in a quartz cuvette to give final concentrations of 1 mM Tz-PEG-OH and 10 mM, 13.3 mM and 16.6 mM, respectively, of ManCyc or ManCp. The reaction was monitored by measuring the absorption of the

• tetrazine at 522 nm. Pseudo-first-order rate constants were determined for every concentration of ManNCyc and ManNCp, respectively, by plotting ln(A0/At) versus time. For the determination of A0, a 1 mM solution of Tz-PEG-OH was used. At is the absorption of the reaction at time point t. Analysis by linear

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• metathesis to proceed efficiently “in water” [36]. Lipshutz and co-workers generalized the application of a three-component non-ionic surfactant for numerous reactions in water, including olefin metathesis [37][38][39]. The surfactant, PTS, incorporates α-tocopherol, sebacic acid and PEG moieties as part of

• analogues (Scheme 8). However, catalysts 1 and 2 are unstable in water and their use is limited to ROMP. Polyethylene glycol (PEG)-tagged catalysts (10 and 11, Figure 1c) showed significantly improved RCM activities in water, but they tend to form aggregates in water due to their high molecular weight (ca

• (Figure 1c) through host–guest interactions [61]. Chung and co-workers used a PEG-tethered adamantyl ligand for various metathesis reactions in water and DCM [62]. The authors showed that the catalyst can be easily removed by generating a host–guest complex between silica-grafted β-cyclodextrin and the

Olefin metathesis in multiblock copolymer synthesis

• Maria L. Gringolts,
• Yulia I. Denisova,
• Eugene Sh. Finkelshtein and
• Yaroslav V. Kudryavtsev

Beilstein J. Org. Chem. 2019, 15, 218–235, doi:10.3762/bjoc.15.21

• -substituted NB with poly(ethylene glycol) (PEG) [69]. Ring-opening metathesis copolymerization of the rather strained cyclooctene (COE) and a strainless 27-membered macrocyclic olefin (MCO) led to the multiblock copolymer consisting of octenylene blocks linked with ring-opened MCO segments (Scheme 6) [70

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• catalyst and carbohydrate or small polyethylene glycol (PEG) groups were attached [11]. As another strategy to modify a protein surface with olefin metathesis, Isarov and Pokorski introduced a Grubbs 3rd generation catalyst on the surface of lysozyme and performed ring-opening metathesis polymerization

• (ROMP) on the protein surface employing a PEGylated norbornene derivative as substrate [13]. This led to proteins modified with PEG chains. These two examples illustrate the potential applications of olefin metathesis in protein modification. Further applications would be the implementation of olefin

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• -cleavable linker. A polyethylene glycol (PEG) linker was selected as PEG linkers demonstrate enhanced water solubility in comparison to alkyl chain linkers. We then had to make a decision on the position of attachment for the PEG linker to compound 1. For siderophore conjugates, it is crucial that the

• suitable position for PEG linker attachment [13]. From commercially available 2-(2-aminoethoxy)ethanol the amine functionality was Boc-protected under standard conditions to give compound 2 (Scheme 1). Under basic conditions 2 underwent an SN2 reaction with commercially available p-xylylene dichloride to

• suitable to progress to the next steps. Initially, the reaction of 3 with chlorpromazine (free base) was attempted at room temperature; however, it was found refluxing was required to drive the reaction to completion to generate compound 4 in excellent yield. The final PEG-amine-functionalised

Calixazulenes: azulene-based calixarene analogues – an overview and recent supramolecular complexation studies

• Paris E. Georghiou,
• Shofiur Rahman,
• Abdullah Alodhayb,
• Hidetaka Nishimura,
• Jaehyun Lee,
• Atsushi Wakamiya and
• Lawrence T. Scott

Beilstein J. Org. Chem. 2018, 14, 2488–2494, doi:10.3762/bjoc.14.225

• Stueker of Compute/Calcul Canada via the Westgrid and Acenet facilities. The late Prof. R. Marceau, Vice-President Research, M.U.N. is gratefully acknowledged for research support to PEG.

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• linker tethering the transporting vehicle to the cytotoxic warhead, d) the “programmable” navigating/targeting moiety (i.e., receptor-specific ligand) and e) the “stealth” carrier (i.e., PEG) transfusing enhanced bioavailability. These modules are encoded in Figure 2A with different colors: the

Crystal structure of the inclusion complex of cholesterol in β-cyclodextrin and molecular dynamics studies

• Elias Christoforides,
• Andreas Papaioannou and
• Kostas Bethanis

Beilstein J. Org. Chem. 2018, 14, 838–848, doi:10.3762/bjoc.14.69

• increased safety in NPC animal models [12]. Moreover, superstructures of cyclodextrins like mono-lactose-appended β-CD [13] and biocleavable pluronic/β-CD-based polyrotaxanes [14] as well as PEG-lipid micelles (DSPE-PEG) in combination with HP-β-CD [15] have shown enhanced therapeutic effects and exhibit a

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• for facile tuning of their properties such as size [13][74], membrane permeability [75] and stability [76]. Various copolymers have been reported for polymersome formation such as poly(ethylene glycol)-b-polystyrene (PEG-b-PS) [14][77], polystyrene-b-polyisocyanopeptide (PS-b-PIAT)[21][22] and poly(N

• conversion of glucose in a tandem reaction [82]. The hydrophilic block of their polymersomes was PEG, and the hydrophobic block contained both poly[2-(diethylamino)ethyl methacrylate] (PDEAEM) which is pH responsive, and poly[4-(3,4-dimethylmaleimido)butyl methacrylate] (PDMIBM) as cross-linker. The activity

• in yields above 70%. Moreover, the Pd@PNIPAM nanoreactors could be easily recycled thanks to the reversible phase-transition of the polymeric brushes [112]. Que et al. reported the synthesis of gold nanoparticles (Au NPs) sheltered in PEG-PS nanogels for the reduction of 4-nitrophenol (4NP) [121

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• as in the A549 and MDA-MB-468 (αVβ3−) cell lines (2.4–3.1 times, cf. entry 1 with entry 5 in Table 3). The cyclo[DKP-isoDGR]-α-amanitin conjugate bearing the lysosomally cleavable Val-Ala linker and a PEG-4 spacer 11 proved slightly more potent than α-amanitin in both the U87 (αVβ3+) and MDA-MB-468

• -amanitin (10) and cyclo[DKP-isoDGR]-PEG-4-Val-Ala-α-amanitin (11). Synthesis of α-amanitin-cyclo[DKP-RGD] and α-amanitin-cyclo[DKP-isoDGR] conjugates 7–10. Reagents and conditions: a) 1. glutaric anhydride, DMAP, iPr2NEt, DMF, overnight, 2. DIC, N-hydroxysuccinimide, DMF, overnight; b) di-N-succinimidyl

• -isoDGR]-PEG-4-Val-Ala-α-amanitin conjugate 11. Reagents and conditions: a) 4-pentynoic acid N-hydroxysuccinimidyl ester, iPr2NEt, DMF, overnight; b) N3-PEG-4-cyclo[DKP-isoDGR], sodium ascorbate, CuSO4·5H2O, DMF/water, rt, overnight. Inhibition of biotinylated vitronectin binding to αvβ3 and αvβ5

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• of the desired products [34][39]. 4. Preparation of trinucleotides on soluble supports Another strategy of combining the advantages of solution chemistry and solid-phase methods is the assembly of oligonucleotides on soluble supports. Among the supports used for this purpose, polyethylene glycol (PEG

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

• -diazopyrazole derivative 158 with 4-substituted benzylidene-3-methyl-1H-pyrazol-5(4H)-one 159 in PEG-400. The reaction resulted in the synthesis of 6,7-dihydropyrazolo[1,5-a]pyrimidine derivatives 160 (Scheme 45). Selected compounds were studied for their interaction with calf thymus DNA using various

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• that were used for self-assembled monolayers (e.g., compound 61 [187]), polymers (PEG derivative 62 [188] or functionalized polyethylene 63 [189]) were reported. The McKenna’s procedure was also applied to prepare polyphosphonic acids as exemplified by the compounds 64 [120], 65 [190], 66 [191] and the

Solid-state mechanochemical ω-functionalization of poly(ethylene glycol)

• Michael Y. Malca,
• Pierre-Olivier Ferko,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2017, 13, 1963–1968, doi:10.3762/bjoc.13.191

• Michael Y. Malca Pierre-Olivier Ferko Tomislav Friscic Audrey Moores Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, H3A 0B8, Canada 10.3762/bjoc.13.191 Abstract Poly(ethylene glycol) (PEG) is a linear polymer with a wide range of applications in chemical

• manufacturing, drug development and nanotechnology. PEG derivatives are being increasingly used to covalently modify small molecule and peptide drugs, as well as bioactive nanomaterials in order to improve solubility in biological serum, reduce immunogenicity, and enhance pharmacokinetic profiles. Herein we

• present the development of mechanochemical procedures for PEG functionalization without the need for bulk solvents, offering a cleaner and more sustainable alternative to existing solution-based PEG procedures. The herein presented mechanochemical procedures enable rapid and solvent-free derivatization of

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• polymeric macromolecular catalysts, e.g., PEG 200 and PEG 10000 as solid auxiliaries to enhance crystallization under LAG mechanochemical conditions in "polymer and liquid-assisted grinding" or POLAG [22][23]. While the focus in these investigations has been on the improvement of the macroscopic parameters