A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• -catalyzed azide–alkyne cycloaddition (CuAAC) for the synthesis of 1,4-disubstituted 1,2,3-triazole derivatives was initially discovered by the groups of Meldal and Sharpless. Then, Ru-catalyzed azide–alkyne cycloaddition (RuAAC), affording selectively 1,5-disubstituted 1,2,3-triazoles, was introduced [38

• irrespective of the nature and position of the substituent [39]. The supposed reaction mechanism for the reaction is shown in Scheme 3. Initially, the presence of bromine as an electron-withdrawing substituent lowers the LUMO energy to facilitate the cycloaddition process of acrolein with organic azide. The

• group compatibility, including using enaminones containing aliphatic and aromatic substituents as well as azide compounds containing electron-donating and -withdrawing groups on the aromatic ring. In all cases, only 4-acyl-substituted regioisomers were obtained (Scheme 4) [40]. The mechanism was also

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• tosylate under basic conditions affording 24 in a yield of 83%. The displacement of the tosyl group with an azide whilst heating the reaction at 80 °C allowed for the isolation of azide 25 in a good yield of 75%. Heating at higher temperatures resulted in product decomposition. Hydrogenation of the azide

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• ]. Nielsen and co-workers [43] synthesized 2′-(4-(thymin-1-ylmethyl)-1,2,3-triazole-1-yl)- and 2′-(4-(N6-benzoyladenine-9-ylmethyl)-1,2,3-triazole-1-yl)-substituted double-headed nucleosides of 2′-deoxy-5′-O-(4,4′-dimethoxytrityl)uridine (14 and 15) from the nucleoside azide 12 which in turn was obtained by

• protection of 16 followed by introduction of an azide group in the C-2′ position of the molecule to afford nucleoside 22. The treatment of azide 22 with pyrrolidine in acetonitrile followed by hydrogenation afforded aminonucleoside 23, which was used as a key intermediate for the synthesis of the double

• the literature [30][32][49]. The spironucleoside 2 was then reacted with sodium azide to afford the arabino-uridine 38 with an azidomethyl group in the C-2′ position. The arabino-uridine 38 was reacted with TBAF and 4,4′-dimethoxytrityl chloride to afford nucleoside 39 which was reacted with 1

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• thioglycosides prepared from deoxyfluorinated 1,6-anhydro-2-azido-β-ᴅ-hexopyranose precursors by ring-opening reaction with phenyl trimethylsilyl sulfide. Nucleophilic deoxyfluorination at C4 and C6 by reaction with DAST, thioglycoside hydrolysis and azide/acetamide transformation completed the synthesis

• donors for the installation of a 1,2-cis-linked multifluorinated GlcNAc and GalNAc moiety. Results and Discussion Our approach to the synthesis is summarized in Scheme 1. Challenging regio- and stereoselective introduction of fluorine at C3 and C4 of the pyranose ring, together with azide installation at

• 1,6-anhydro derivative 10, we were able to isolate one of the side-products in sufficient purity and quantity to assign the structure of C-furanoside 20 (Scheme 2). This compound resulted from pyranose ring contraction probably caused by intramolecular displacement of the C2 azide aided by

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• (sp3)–H bromination reaction. The proposed reaction mechanism is shown in Scheme 5, which involves the following steps. (1) The reaction between NBS and TMSN3 generates bromine azide via the elimination of N-(trimethylsilyl)succinimide [52][53]; (2) bromine and azide radicals are then formed via

• homolytic cleavage of the weak Br–N3 bond in bromine azide [54][55]; (3) the bromine radical can also be generated from NBS with the formation of a succinimide radical; (4) alkyl radical intermediate A is then formed via hydrogen abstraction by the succinimidyl radical and/or azidyl radical [56][57]; (5

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• , promoted by irradiation with visible light. In 2017, Shirke and Ramaastry [40] proposed an organic catalyzed β-azide reaction of ketene 155 initiated by the EDA complex formed by DABCO and Zhdankin reagent 156 (Scheme 54). A variety of β-azidoketones was conveniently obtained with good to excellent yield

• initiated by an EDA complex. Synthesis of boration product 151 initiated by an EDA complex. Synthesis of boronic acid ester derivative 154 initiated by an EDA complex. Synthesis of β-azide product 157 initiated by an EDA complex. Decarboxylation reaction initiated by an EDA complex. Synthesis of amidated

Synthesis of β-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles

• Soumyaranjan Pati,
• Renata G. Almeida,
• Eufrânio N. da Silva Júnior and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2021, 17, 762–770, doi:10.3762/bjoc.17.66

• Meldal have independently developed a copper-catalysed azide–alkyne cycloaddition that accelerated the rate of the reaction and allowed the selective preparation of 1,5-disubstituted 1,2,3-triazoles [16][17][18][19]. As noted above, a wide range of methods are available in the literature for the

• -triazoles with alkynes and Rh catalysed N1 and N2 selective alkylations [24][25]. As for metal-free approaches, besides synthesizing N-alkylated triazoles via 1,3-dipolar cycloaddition of alkyl azide with enols generated from carbonyl compounds under transition metal-free conditions [26], a direct

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• modifications were introduced into the DNA backbone using the Staudinger reaction between the 3’,5’-dinucleoside β-cyanoethyl phosphite triester formed during DNA synthesis and sulfonyl azides, 4-(azidosulfonyl)-N,N,N-trimethylbutan-1-aminium iodide (N+ azide) or p-toluenesulfonyl (tosyl or Ts) azide, to

• Synthesis and purification of modified ONs 4-(Azidosulfonyl)-N,N,N-trimethylbutan-1-aminium iodide [38] and tosyl azide (p-toluenesulfonyl azide, TsN3) [39] were synthesised and used for the synthesis of the modified ONs using an automated DNA synthesiser as described. The solution of sulfonyl azide (0.5 M

• yield was also improved by minimising the handling of the solid support and performing the reaction using a microtube pump to deliver the sulfonyl azide solution onto the column with CPG support. The cleaved and deprotected N+- and Ts-ONs were initially purified using reversed-phase (RP) HPLC. However

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols

• Emine Salamci and
• Yunus Zozik

Beilstein J. Org. Chem. 2021, 17, 705–710, doi:10.3762/bjoc.17.59

• the corresponding cyclic sulfate via the formation of a cyclic sulfite in the presence of catalytic RuO4. The reaction of this cyclic sulfate with a nucleophilic azide followed by the reduction of the azide group provided the target, 3-aminocyclooctanetriol. The second key compound, bromotriol, was

• prepared by epoxidation of the cyclooctenediol with m-chloroperbenzoic acid followed by hydrolysis with HBr(g) in methanol. Treatment of bromotriol with NaN3 and the reduction of the azide group yielded the other desired 3-aminocyclooctanetriol. Hydrolysis of the epoxides with HCl(g) in methanol gave

• with sodium azide of the corresponding cyclic sulfate intermediate 9, which contains the only stereocentre. The cyclic sulfate 9 could be synthesized from diacetatediol 7 [33]. For this purpose, the reduction of the endoperoxide 5 with zinc followed by acetylation of the hydroxy group and OsO4/NMO

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• followed by microwave-assisted intramolecular azide–alkyne cycloaddition (IAAC) gave a series of target heterocyclic compounds in moderate to excellent yields. Surprisingly, the normally required ruthenium-based catalysts were found to not affect the IAAC, only making isolation of the target compounds

• to a large number of diverse heterocyclic compounds [10][11]. Over the past decade, several cases of using an Ugi four-component reaction (Ugi-4CR) in combination with intramolecular azide–alkyne cycloaddition (IAAC) for the synthesis of 1,2,3-triazolobenzodiazepines were reported [3][7][12][13][14

• includes a [3 + 2] click reaction between the azide ion with the triple bond and further C–N coupling instead of the IAAC reaction. Compounds having no fused benzene ring or with a heterocyclic moiety instead could also be obtained via the tandem approach Ugi reaction/IAAC [15][16]. Despite the

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• of purine [73][74][75][76] or alkylation of inosine or guanosine derivatives (Ib→II, Scheme 1) [30][36]. In the next step, azide can be introduced either by a second SNAr reaction on the C2-halo derivative or by diazotization/azidation at C2. Then, the Cu(I)-catalyzed azide–alkyne cycloaddition

• reactions at C(6) (V→VI→IV, Scheme 1) [11][14][62][63][77][78]. The main advantage of pathway B is a straightforward access to 2,6-diazidopurines V and 2,6-bistriazolylpurines VI due to excellent nucleophilic properties of the azide ion and well-established CuAAC reaction. Pathway B also avoids performing

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• ) as the azide donor to facilitate the generation and immediate use of the intermediate acyl azide that would rearrange to an isocyanate upon heating. Toluene was chosen as a suitable solvent providing good solubility of the acid substrates (1 M) in the presence of triethylamine (1.0 equiv

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