A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• ]. Similarly, Maurya developed a microfluidic photoreactor for the synthesis of a fused β-carboline from an α-ketovinyl azide and a 1,2,3,4-tetrahydro-β-carboline (Scheme 1b) [30]. More recently, Kappe reported the generation of 2H-azirines under continuous flow conditions, and their transformation into

• approach that enables the direct preparation of functionalized NH-aziridines from vinyl azides. Results and Discussion At the earliest stage of our research, we focused on the choice of the most suitable solvent for azide cyclization and organolithium addition reactions. Most of the previously reported

• to 16 min, respectively. The complete transformation of vinyl azide 1a was therefore achieved above the boiling point of CPME (106 °C), as enabled by the utilization of a microfluidic reactor. From a technical point of view, the pressure generated during the course of the reaction, due to nitrogen

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• chlorine at the purine C2 position by azide, and 3) copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) with different alkynes. Pathway B included: 1) the two-step synthesis of 2,6-bistriazolylpurine derivatives 6 from 2,6-dichloropurine derivative 1 [22] and 2) the SNAr–Arbuzov reaction with

• to optimize the Cl→N3 SNAr process at the purine C2 position, and that way, the isopropyl phosphonate 2b was also obtained. It is known that both chloride and azide can cleave phosphonate esters [25][26][27][28], but the chloride source would not interfere with the SNAr process at C2. Hence, we

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• Schwartz’s reagent-mediated reductive amide functionalization followed by a variant of the Ugi–azide multicomponent reaction. The anomeric configurations of two products were unambiguously confirmed by X-ray analysis. This work also describes examples of interesting further transformations of the title

• one-pot Mannich/Michael sequence leading to oligocyclic compounds [24], and employment in subsequent Joulié–Ugi multicomponent reactions [25]. This work is an extension of these efforts and seeks to investigate the possibility of incorporating the Ugi–azide multicomponent reaction in this workflow. A

• standard Ugi–azide reaction conditions [35][36][37][38][39] in a one-pot, tandem process. Subjecting glucose-derived lactam 1 to such a procedure gave the desired product in good yield, but with virtually no diastereoselectivity, as shown in Scheme 2. Optimization and scope An initial optimization study

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• structures modified with sulfate groups, and their capability to interact with biological components has been demonstrated recently [31][32]. In this work, we therefore coupled dPGS to C2-symmetrical discotic peptide amphiphiles using copper-catalyzed azide alkyne cycloaddition chemistry. The evaluation of

• I was purified by size exclusion chromatography. In order to synthesize the sulfated, functionalized supramolecular building block II, we made use of the selective heterofunctionalization of trimesic acid. By replacing one of the solubilizing dodeca(ethylene glycol) moieties with an azide group

• , post-functionalization using a subsequent copper-catalyzed azide–alkyne cycloaddition reaction became accessible [35][36]. At the same time the other two unmodified side arms of the dendritic amphiphile make sure that the fidelity of the β-sheet motifs and directed supramolecular polymerization remains

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• accomplished, followed by the reductive workup of the resulting selenoxide and an increase in its temperature, eliminating selenoxide to generate carboxylic acid (−)-83 in 90% yield. This acid was subjected to Curtius rearrangement [55] in the presence of DPPA as a source of azide, providing isocyanate (−)-84

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• to give the desired bicyclic [3.3.0] aldehyde 124 in 88% yield. A seven-step synthesis from aldehyde 124 gave azide 125. It was converted to alcohol 126 in seven steps. Alcohol 126 was treated with LDA and vinylMgBr to facilitate a γ-OH directed 1,4-addition [63] to give C-7-vinylated tricycle 127 in

Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides

• Vladimir Ilkin,
• Vera Berseneva,
• Tetyana Beryozkina,
• Tatiana Glukhareva,
• Lidia Dianova,
• Wim Dehaen,
• Eugenia Seliverstova and
• Vasiliy Bakulev

Beilstein J. Org. Chem. 2020, 16, 2937–2947, doi:10.3762/bjoc.16.243

• Beckmann reaction of oximes with p-toluenesulfonyl azide [34], the sulfonyl ynamide rearrangement by treatment with amines [35], the sodium iodide catalyzed reaction of sulfonamide with formamide [36], and the condensation of sulfonamide derivatives with DMF–DMA [37]. A few representatives of N-sulfonyl

• have found that 1-butyl-1,2,3-triazole-4-carbothioamide (1c) reacts well with benzenesulfonyl azide (2c) in various solvents to form the desired 1-butyl-1,2,3-N-sulfonyl amidine 3n in diverse solvents such as n-butanol, n-propanol, toluene, ethanol, water and even under solvent-free conditions (see

• Table 1 for the yields and other circumstances). From these data we can conclude that the yield of the final product is optimal for the reaction under solvent-free conditions. 1-Butyl-1,2,3-triazole 1с reacts faster than 1,2,3-triazole-4-carbothioamide 1f while using a lower amount of a sulfonyl azide

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

• ), or sodium azide (known mutagen for TA 100), was also examined using the plate incorporation procedure and the results are summarized in Table 2 and Table 3. This assay proved a strong antimutagenic activity of all tested α-(arylamino)acetonitrile derivatives, with a better inhibition exhibited in the

• mutagenic compounds such as 2-aminoantracene and sodium azide. Experimental General procedures for the preparation of 2-(arylamino)-2-(hetero)arylacetonitrile derivatives Ultrasound-assisted reaction conditions (a) Ultrasound-assisted reactions were carried out by indirect sonication using a commercially

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• RNA in a highly selective and efficient way. The more traditional strategies rely on reaction of isothiocyanates or NHS esters with aliphatic amines [13][14], or on addition of thiols to the α,β-unsaturated carbonyl face of maleimides [15]. Over the past years, the copper catalyzed alkyne–azide

• cycloaddition (CuAAC) became very popular [16]. A variant of this, the strain-promoted alkyne–azide cycloaddition (SPAAC) even offers the possibility of in cell application, as applies also to the inverse electron-demand Diels–Alder reaction (IEDDA) [17][18]. In vitro, often a combination of orthogonal methods

Using multiple self-sorting for switching functions in discrete multicomponent systems

• Amit Ghosh and
• Michael Schmittel

Beilstein J. Org. Chem. 2020, 16, 2831–2853, doi:10.3762/bjoc.16.233

• binding site to nanoswitch [Cu(68)]+ preventing its action as an organocatalyst (OFF-1), while the copper catalyst [Cu(69)]+ was available to catalyze a click reaction between 4-nitrophenylacetylene (47) and benzyl azide (46) (ON-2). The addition of 1 equiv of phenanthroline 69 to the state SelfSORT-I

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• Na-cacodylate buffer were used to prepare analyte solutions with different ligand:DNA ratios (LDR = 0.00, 1.25, 2.50, 5.00). Synthesis General procedure (GP) [54] To a solution of the berberine azide derivatives 3a–e (1.0 molar equiv) and 9-propargyladenine (2, 1.1 molar equiv) in THF/MeCN 2:1 was

Easy access to a carbohydrate-based template for stimuli-responsive surfactants

• Thomas Holmstrøm,
• Daniel Raydan and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2020, 16, 2788–2794, doi:10.3762/bjoc.16.229

• steps [20]. Subjecting the Černý epoxide to sodium azide at an elevated temperature in a mixture of DMF and water afforded the diazide 3 in a 76% yield [21][22]. The presence of the azido groups was supported by a band at ≈2100 cm−1 in the FTIR spectrum of the diazide 3. The 1,6-anydro functionality

• ]. Furthermore, starting from the azide 8, it was possible to achieve ester functionalities by a CuAAC reaction [23][24] in the presence of the two different alkynes 14 and 15, giving rise to the diester derivative 12 and the tetraester derivative 13 (Scheme 2). Subsequently, the esters could be hydrolyzed by

Optical detection of di- and triphosphate anions with mixed monolayer-protected gold nanoparticles containing zinc(II)–dipicolylamine complexes

• Lena Reinke,
• Julia Bartl,
• Marcus Koch and
• Stefan Kubik

Beilstein J. Org. Chem. 2020, 16, 2687–2700, doi:10.3762/bjoc.16.219

• synthesized in the racemic and the enantiomerically pure form. The racemate rac-1 was obtained in four steps from triethylene glycol monomethyl ether by tosylation, substitution of the tosyl by an azide group, and reduction to obtain the corresponding amine (Scheme 1). This amine was coupled to racemic lipoic

Synthesis and characterization of S,N-heterotetracenes

• Astrid Vogt,
• Florian Henne,
• Christoph Wetzel,
• Elena Mena-Osteritz and
• Peter Bäuerle

Beilstein J. Org. Chem. 2020, 16, 2636–2644, doi:10.3762/bjoc.16.214

• nitrogen heteroatoms were synthesized in multistep synthetic routes. A Buchwald–Hartwig amination of brominated precursors, thermolysis of azide precursors, and a Cadogan reaction of nitro-substituted precursors were successfully applied to eventually build-up pyrrole rings to stable and soluble fused

• of azide precursors, and a Cadogan cyclization of nitro-substituted precursors were applied to prepare various unknown derivatives. These represent novel core molecules, which by further derivatisation, for example with terminal acceptor groups, would lead to interesting π-conjugated materials for

• (Scheme 1). Synthesis of S,N-heterotetracene H-SN4 13 by thermolysis of azide precursors. Smaller parent heterotriacene dithienopyrrole (H-DTP) was first synthesized by Zanirato et al. by thermolysis of 3-azido-2,2’-bithiophene as the key step [9]. We therefore tried to build up tetracyclic H-SN4 13 via

Design and synthesis of a bis-macrocyclic host and guests as building blocks for small molecular knots

• Elizabeth A. Margolis,
• Rebecca J. Keyes,
• Stephen D. Lockey IV and
• Edward E. Fenlon

Beilstein J. Org. Chem. 2020, 16, 2314–2321, doi:10.3762/bjoc.16.192

• alkyne–azide click cycloaddition as the linking step, and ester saponification as the cutting step [13][21] (Supporting Information File 1). The target trefoil knot using host 1 and guest 2 is shown in Figure 2c. The binding event during the double-threading step was modeled after previous literature

• ), whereas host 1 and guest 3 would lead to a 75 backbone-atom trefoil (and unknotted macrocycle). Results and Discussion The synthesis of bis-macrocyclic host 1 began by breaking the symmetry of naphthalene-1,5-diol (4) by alkylation of one of the alcohols with 2-azidoethyl mesylate to yield azide 5 in 27

• reaction with ethylene carbonate using a modified literature procedure (see Supporting Information File 1). Conversion of 7 to bismesylate 8 proceeded smoothly in 92% yield under standard conditions. The symmetry-breaking step in this route involved treatment of 8 with one equivalent of sodium azide in

Access to highly substituted oxazoles by the reaction of α-azidochalcone with potassium thiocyanate

• Mysore Bhyrappa Harisha,
• Pandi Dhanalakshmi,
• Rajendran Suresh,
• Raju Ranjith Kumar and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2020, 16, 2108–2118, doi:10.3762/bjoc.16.178

• ; potassium persulfate; thiazole; vinyl azide; Introduction Vinyl azide is one of the most versatile and potent building blocks explored in the synthesis of several heterocycles [1][2][3][4][5]. It can undergo photolysis or thermolysis to afford highly strained three-membered 2H-azirine, which can act as the

• -trisubstituted oxazoles 3. Reaction of vinyl azide 1 and 3 with ferric nitrate. Reactions were carried out at reflux temperature, using 1 (1 mmol), 2 (3 mmol), ferric nitrate (0.5 mmol) in acetonitrile (2 mL) for 6 h. Yields refer to the pure products after column chromatography. Optimisation studies.a Screening

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• produced 46. The hydrozirconation of 46 with Schwartz’s reagent under equilibrating conditions, followed by the reaction with I2 gave the vinyl iodide 47. Finally, the activation of the C-14 hydroxy group and the SN2 displacement with azide gave the C-8–C-16 fragment 48. Ghosh relied on a reductive

• , followed by a transmetalation provided a vinylzinc reagent that was coupled with 48 to afford 128, for which only the E-stereoisomer was observed. Notably, the Negishi conditions were tolerant to the azide present in 48 and the oxirane and 1° iodoalkane present in 91. The subsequent reduction of the azide

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• phthalimidoyl substituents affording preferentially the Z-isomer of 1c. However, heteronucleophiles such as sodium azide, secondary amine and cesium fluoride were unsuccessfully tested. Finally, using the conditions developed by Burkhard and Carreira [26], the opening of the fluoroalkylidene-oxetane ring was

• alkenes E-1d and E-9, was studied either on the bromomethyl (CH2Br) or on the hydroxymethyl (CH2OH) arm, when applicable. First, from a mixture of lactones 15 and 19 substitution on the bromomethyl arm was performed using sodium azide (Scheme 7). The reaction proceeded smoothly in DMF but it proved

• corresponding chloride (not shown). An Arbuzov reaction was performed directly on the allylic bromide obtained by treatment of 27 with LiBr (5 equiv), to give the phosphonate 29 in 76% overall yield. Finally, azide 28 was obtained in 89% yield in two steps from the non-isolated intermediate mesylate 27. After

Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents

• Paola Vitale,
• Luciana Cicco,
• Ilaria Cellamare,
• Filippo M. Perna,
• Antonio Salomone and
• Vito Capriati

Beilstein J. Org. Chem. 2020, 16, 1915–1923, doi:10.3762/bjoc.16.158

• prepared from the same phenacyl azide as starting material by properly selecting the nature of the eutectic mixture and the temperature, in the presence or absence of bases. To the best of our knowledge, while there are a few reports for the synthesis of 2-aroylimidazoles (a) through the condensation of α

• symmetrical pyrazines, we observed that phenacyl bromide (1a, 1.5 mmol) could be almost quantitatively converted into phenacyl azide (2a, 97% yield), within 4 h, when treated with NaN3 (1.65 mmol) as the azide source in a choline chloride (ChCl)/glycerol (Gly) (1:2 mol/mol) eutectic mixture at room

• reaction, and thus they could be isolated by simple decantation or centrifugation and washing with a few drops of EtOAc or Et2O. This procedure left azide 2a in solution. The latter could be quantified (10% yield) by simple dilution with an equal volume mixture of water and EtOAc, followed by the

Nonenzymatic synthesis of anomerically pure, mannosyl-based molecular probes for scramblase identification studies

• Giovanni Picca,
• Markus Probst,
• Simon M. Langenegger,
• Oleg Khorev,
• Peter Bütikofer,
• Anant K. Menon and
• Robert Häner

Beilstein J. Org. Chem. 2020, 16, 1732–1739, doi:10.3762/bjoc.16.145

• moiety for photocrosslinking to MPD-recognizing proteins. The presence of an additional propargyl group provides a way to further derivatize the probe with biotin azide via click-type chemistry [16] for the isolation of protein–lipid adducts using streptavidin resins [10]. To synthesize such molecular

Synthesis of Streptococcus pneumoniae serotype 9V oligosaccharide antigens

• Sharavathi G. Parameswarappa,
• Claney L. Pereira and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2020, 16, 1693–1699, doi:10.3762/bjoc.16.140

• derived from acceptor 19. To circumvent the challenging β-mannosylation, the mannosamine unit was installed via the C-2 inversion of glucose at the trisaccharide stage. For that purpose, the C-2 levulinate ester in compound 22 was removed and the resulting secondary alcohol 23 was converted to the azide

• via a two-step process of triflation and azide substitution to produce the desired trisaccharide 24 [29]. Removal of the allyl group using iridium-catalyzed isomerization and subsequent treatment with iodine in the presence of water yielded trisaccharide acceptor 25 for the late stage [2 + 3

• + 3] glycosylation of 25 with 29 furnished exclusively the α-anomer of the pentasaccharide 30 in 73% yield (Scheme 4). The subsequent conversion of the azide to acetamide was achieved in one step using thioacetic acid to afford the protected pentasaccharide 31. The final transformation included the

Clickable azide-functionalized bromoarylaldehydes – synthesis and photophysical characterization

• Dominik Göbel,
• Marius Friedrich,
• Enno Lork and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2020, 16, 1683–1692, doi:10.3762/bjoc.16.139

• , Germany Institute for Inorganic and Crystallographic Chemistry, University of Bremen, Leobener Straße NW2, 28359 Bremen, Germany 10.3762/bjoc.16.139 Abstract Herein, we present a facile synthesis of three azide-functionalized fluorophores and their covalent attachment as triazoles in Huisgen-type

• cycloadditions with model alkynes. Besides two ortho- and para-bromo-substituted benzaldehydes, the azide functionalization of a fluorene-based structure will be presented. The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of the so-synthesized azide-functionalized bromocarbaldehydes with terminal

• alkynes, exhibiting different degrees of steric demand, was performed in high efficiency. Finally, we investigated the photophysical properties of the azide-functionalized arenes and their covalently linked triazole derivatives to gain deeper insight towards the effect of these covalent linkers on the

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts

• Soundararajan Karthikeyan,
• Radha Krishnan Shobana,
• Kamarajapurathu Raju Subimol,
• J. Helen Ratna Monica and
• Ayyanoth Karthik Krishna Kumar

Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130

• attack on the AzPS by the allylic alcohol of the MBH adduct Ia. Subsequently, the azide ion undergoes a nucleophilic attack on the allylic carbon atom of the oxyphosphonium intermediate IIa and generates the 2-azidoalkene IIIa. Interestingly, the consecutive nucleophilic attack by the azido ion smoothly

• the presence of CuI (5 mol %), triphenylphosphine (1 equiv), bromomethane (1.1 equiv), and sodium azide (2 equiv). Unexpectedly, the reaction yielded (Z)-methyl-2-(bromomethyl)-3-phenylacrylate (58%) over the expected triazole. Similarly, the MBH adduct derived from furan, 1i, and phenylacetylene (2b

• phosphonium salts As described in [49]. Typically, triphenylphosphine, bromomethane, and sodium azide at a molar ratio of 1.1:1.1:5 were utilized for synthesising the quaternary phosphonium salt. Initially, triphenylphosphine and sodium azide were stirred at 0 °C in dimethylformamide (5 mL) for 30 minutes. To

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review

• Alessandra Del Tito,
• Havall Othman Abdulla,
• Davide Ravelli,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 1476–1488, doi:10.3762/bjoc.16.123

• onto a vinyl azide (see the case of 16.1 in Scheme 16). Different radicals were used for this purpose. As an example, an α-carboxyethyl alkyl radical was formed from the corresponding α-bromoester under white LED irradiation in the presence of an IrIII-based photocatalyst. The addition of this

• intermediate onto the C–C double bond of 16.1 gave radical 16.2·a upon nitrogen loss, which underwent an intramolecular cyclization and finally afforded the substituted phenanthridine 16.3a in a satisfactory yield (Scheme 16, path a) [81]. The same azide 16.1 underwent trifluoromethyl radical addition to give

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• -thiofuranoside 141 was prepared from methyl 2,3-anhydro-α-D-ribofuranoside (133a), which was first reacted with sodium azide followed by the similar synthetic route as described above, affording 3,5-anhydro-2-azido-3-thiofuranoside 139. The azido derivative 139 generated the final product 2-amino-3,5-anhydro-3

• chloromethylthiirane (epithiochlorohydrin, 398a), with hard and weak nucleophiles [105][106][107][108][109], including phenoxides [105], carboxylates and dicarboxylates [106][107], potassium cyanide, sodium azide, hydroxylamine, trifluoromethanesulfonamide, and pyridine [108]. However, the method could only applied to