Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• together all necessary functionalities for further transformations. The Ugi adducts were then subjected to a base-induced ring closing and an intramolecular azide–alkyne cycloaddition reaction in succession to obtain highly fused benzodiazepine frameworks. Keywords: benzodiazepine; 2,5-diketopiperazine

• ; hydantoin; intramolecular azide–alkyne cycloaddition; Ugi reaction; Introduction The versatile bioactivities of multiring-fused heterocyclic scaffolds continue to attract significant attention in developing new methods for their synthesis. A plethora of functionalized fused heterocycles can be easily

• multicomponent reactions with intramolecular azide–alkyne cycloaddition (IAAC) for the generation of triazole-fused heterocycles [12][13][14][15][16][17][18][19][20][21][22][23]. In this report we disclose our results on the development of a sequential synthetic approach involving Ugi 4-component reaction (4-CR

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• from vinyl azides through an azirine intermediate (Scheme 3). The process starts with the generation of the azirine from the vinyl azide by thermolysis. Formation of azirines from vinyl azides by photolysis and thermolysis in continuous flow has been previously described [38][39]. The azirine

• fully continuous process are described in detail. Results and Discussion Thermolysis of the vinyl azide and oxazole formation. Batch optimization The reaction conditions for the thermolysis of the vinyl azide and the subsequent ring expansion of the intermediate azirine to form the oxazole ring were

• initially optimized in batch. For these experiments, vinyl azide 1a was used as a model substrate. The small-scale batch thermolyses were carried out using sealed 1.5 mL vials heated in an aluminum platform. A 0.5 M solution of substrate 1a was prepared using acetone as the solvent. The experiments were

Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines

• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 416–429, doi:10.3762/bjoc.14.30

• the GlcNAc acceptor has an azide or sulfonamide at position 2, rather than acetamide or N-phthalamide. Scheme 5 shows an example of the synthesis of a modified core N-glycan tetrasaccharide oxazoline from the several reported by Wang [77] using this approach. In this case following formation of the

• the incorporation of tags into the glycan structure, which allows further modifications to be made later. In this case, following conversion of the azide at position 2 of the glucosamine unit into an acetamide, azide was introduced at position 6 of the two terminal mannose residues. Protecting group

• interconversions, and peracetylation were followed by conversion to the oxazoline, using TMSBr, BF3·Et2O and collidine, and finally deacetylation. It was found that the incorporated azide was tolerated by the ENGase enzyme (Endo A), and so a modified glycoprotein (RNase) was made by enzymatic attachment of this

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

• disulfide linker in the cytoplasm. In another example, Perrin and co-workers conjugated the N-propargylasparagine of an amanitin analog to a cycloRGD integrin ligand (cyclo[RGDfK]) using a copper-catalyzed azide–alkyne cycloaddition [8]. The conjugates were tested in the U87 glioblastoma cell line, but only

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

• -azidomethylbenzoyl)-protected nucelosides, followed by removal of the 5'-O-DMTr group and extension of the dimer to the trimer by coupling of another N-acyl-3'-O-(o-chlorophenylphosphate)nucleoside. The final removal of the 2-azidomethylbenzoyl group occurred by reduction of the azide with triphenylphosphine in

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• high background. The masking of fluorophores by a more stable group, such as azides, is more attractive. Unfortunately, the phosphine probe generally required for the unmasking of the azide probe is susceptible to rapid aerobic oxidation. Accordingly, new developments in this area are still required

• . One promising example is the release of fluorophores by a phosphine-free photocatalyzed reduction of a self-immolative azide-based linker [105]. Single-labeled PNA probes with additional interacting partners PNA-based strand displacement probes Strand displacement probes consist of a fluorescence

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• -methacryloylbenzamides is similar and includes alkyl substituents on the nitrogen atom and electron-rich and poor aromatic moieties. Mao and Zhou applied vinyl azides for the radical cross-coupling with sodium sulfinate salts (Scheme 56) [95]. They observed that the azide moiety decomposes during the reaction (loss of

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• starting from azide 1 by first protecting the 3-OH group with an allyloxycarbonyl (Alloc) protecting group followed by regioselective reductive opening of the 4,6-O-benzylidene acetal using NaCNBH3 and HCl in diethyl ether, and successive phosphitylation of the liberated 4’-OH functionality with N,N

• deprotected by treatment with tetrabutylammonium fluoride buffered with acetic acid, and the resulting lactol was converted to the imidate donor 11 which was coupled to the orthogonally protected acceptor, an azide 12, using triflic acid as promotor (Scheme 2). Subsequent hydrolytic cleavage of the

• azide 12 with the imidate donor 43 furnished fully orthogonally protected βGlcN(1→6)GlcN 44. Next, the 2’-N-Fmoc group in 44 was removed by treatment with DBU and the first unusual branched acyloxyacyl residue was installed. For the preparation of (R)-3-hydroxy-13-methyltetradecanoic and (R)-3

Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• glycoscience. In this review we present recent advances made in the use of one type of click chemistry, namely the azide–alkyne Huisgen cycloaddition, for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles. Keywords: azide–alkyne Huisgen cycloaddition; carbohydrates

• functionalized carbohydrates (Figure 1c). Various types of reaction, such as reductive amination [32], oxime formation [33], amidation [34], and perfluorophenyl azide (PFPA) photocoupling [35][36], have been used to functionalize the surface of AuNPs with carbohydrates. The detailed information regarding the

• synthesis and application of GAuNPs can be found in the reviews by Penadés and co-workers [9][26] and also in a recent review by Compostella et al. [10]. In this regard, azide–alkyne click chemistry is an attractive approach that could be used to synthesize GAuNPs. The functionalization of AuNPs using the

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds

• Alexey M. Starosotnikov,
• Dmitry V. Shkaev,
• Maxim A. Bastrakov,
• Ivan V. Fedyanin,
• Svyatoslav A. Shevelev and
• Igor L. Dalinger

Beilstein J. Org. Chem. 2017, 13, 2854–2861, doi:10.3762/bjoc.13.277

• Discussion The only method for the synthesis of 1 described so far deals with the reaction of commercially available 2-chloro-3,5-dinitropyridine (4) with NaN3 followed by thermolysis of the intermediate azide [25][26]. We developed an alternative safe and efficient method for the synthesis of 1 starting

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• tetrazoles. Even photo-crosslinking moieties were enzymatically transferred to the N7-position of the mRNA cap from suitable AdoMet analogues. Notably, quantitative modification at the N7-position was achieved [96]. Diazirine and aryl–azide photo-crosslinker moieties were functional showing cross-linking to

• ) followed by treatment with aqueous ammonia (rt, 3 h). Click chemistry for the preparation of capped RNA and cap analogues. (A) Preparation of capped RNA via a copper-catalyzed azide–alkyne cycloaddition (CuAAC) of an azido-modified cap analogue with a 5'-alkyne bearing RNA [120]. (B) An alkyne-modified

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• the presence of the organic photocatalyst N-methyl-9-mesitylacridinium (17), CF3SO2Na was converted into CF3• upon visible-light irradiation. The CF3• radical reacted with the vinyl azide to give the iminyl radical 18 that was reduced by Mes-Acr• (Mes-Acr: 9-mesityl-10-methylacridinium) into the

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• reacted easily in a SN2 reaction to give a more functionalized molecule. For example, treatment of the chlorinated monofluoroalkene with NaN3 provided the corresponding N3-containing monofluoroalkene. The azide group underwent a 1,3-dipolar cycloaddition to give a 1,2,3-triazole, which is also a peptide

• with excellent selectivity (Scheme 4) [28]. The chromium-mediated coupling of 1-bromo-4-(tert-butyldiphenylsiloxy)-1,1-difluorobutane (15) with aldehyde 16 led to the formation of monofluoroalkene 17. This was then reacted with sodium azide and a further Staudinger reduction gave 18. Boc protection of

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• bearing 1,5-disubstituted tetrazoles. Our strategy was accomplished in only three steps: first, a one-pot hydrazino-Ugi-azide four-component reaction; second a hydrazinolysis and finally an additional hydrazino-Ugi-azide reaction. This sequence provides the title compounds in moderate to excellent yields

• ); Ugi-azide reaction; Introduction Tetrazoles are extensively studied, useful non-natural heterocyclic skeletons with the highest nitrogen content among the stable heterocycles [1][2]. The tetrazole-ring system has a variety of applications in organic chemistry, coordination chemistry, and agriculture

• tetrazoles are intermolecular cycloaddition reactions and isocyanide-based multicomponent reactions (IMCRs). Indeed, the Ugi-multicomponent reaction using TMSN3 (trimethylsilyl azide) as acid component, originally reported by Ugi in 1961 [10], is one of the best and most general methods for the synthesis of

¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• give [1,2-15N2]-tetrazolo[5,1-c][1,2,4]triazine 11-15N2. Indeed, [2,3-15N2]-tetrazolo[1,5-b][1,2,4]triazin-7-one 13-15N2 was obtained (see below). Most likely, tetrazole 11-15N2 underwent a ring-opening process, yielding azide 12-15N2, and this process was followed by an alternative ring closure. This

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• substituents in the Cα-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional

• intriguing versatility as building blocks in organic and medicinal chemistry, as their reactivity is unique. Their chemistry involves several highly selective reactions, e.g., [3 + 2] cycloadditions with azides and isoelectronic functional groups (among them the copper or ruthenium-catalyzed azide–alkyne

• to be protected against nucleophiles, bases and deprotonation. According to the approach of Ye et al., a 3-bromopropyl side chain was used, which was converted to the azide and further transformed into an aminoalkyl group by Staudinger reduction [16]. In order to follow a more convergent approach and

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• (R in the 4-position of the ring), which was attributed to an equilibrium of azide–tetrazole. In the solid state, all compounds were found as 2-azidopyrimidines. The regiochemistry of the reaction and the stability of the products are discussed on the basis of the data obtained by density functional

• theory (DFT) for energetic and molecular orbital (MO) calculations. Keywords: 5-aminotetrazol; azide–tetrazole equilibrium; 2-azidopyrimidine; β-enaminones; tetrazolo[1,5-a]pyrimidine; trifluoromethylatedtetrazolo[1,5-a]pyrimidines; Introduction Tetrazolo[1,5-a]pyrimidines have attracted attention in

• 1960s and 1970s reported the existence of an azide–tetrazole equilibrium in many heterocyclic systems, namely tetrazolopyridines, tetrazolopyridazines, tetrazolopyrimidines, tetrazoloazines, and tetrazolopurines. Both tetrazole and azide have different chemical properties. Among other factors, the

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• reactions, with up to a 15-fold gain in yield. Efficiency of both solution and milling procedures depended on the p-substituent in the azide reactant, resulting in H < Cl < Br < I reactivity bias. Solid-state catalysis using Cu(II) and Cu(I) catalysts entailed the direct involvement of the copper species in

• spin resonance (ESR) spectroscopy; in situ Raman monitoring; mechanochemistry; quinoline; solid-state click chemistry; Introduction The copper-catalyzed azide–alkyne cycloaddition (CuAAC) represents a prime example of click chemistry. Click chemistry describes “a set of near-perfect” reactions [1] for

• bond bioisosteres made the click reaction a valuable synthetic methodology for conjugation of bioactive molecules [7][8][9] aiming to improve their biological activities [4][10][11]. Discovery of copper(I) ion catalysis in azide–alkyne cycloadditions was decisive for applications of this reaction, as

Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines

• Satoru Mori and
• Norio Shibata

Beilstein J. Org. Chem. 2017, 13, 2273–2296, doi:10.3762/bjoc.13.224

• TFEO-ZnPc 4 and fluorinated polymer 22 were condensed by a click reaction between azide and alkyne groups (Scheme 8). The graft ratio of the TFEO-ZnPc-supported fluoropolymer was calculated from the area ratio of 19F NMR, and the resulting fluorinated copolymers showed different grafting ratios (from

Superstructures with cyclodextrins: Chemistry and applications IV

• Gerhard Wenz

Beilstein J. Org. Chem. 2017, 13, 2157–2159, doi:10.3762/bjoc.13.215

• magnetic resonance imaging (MRI) [22]. Well-defined fluorescent polyrotaxanes with alternating, threaded cucurbit[6]uril and CD rings were assembled by Fraser Stoddart’s group via an alkyne–azide click reaction exploiting supramolecular catalysis [23][24]. The concurrent radical copolymerization of 1,3

An efficient synthesis of a C₁₂-higher sugar aminoalditol

• Łukasz Szyszka,
• Anna Osuch-Kwiatkowska,
• Mykhaylo A. Potopnyk and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2017, 13, 2146–2152, doi:10.3762/bjoc.13.213

• building blocks. The synthesis was realized by a regioselective introduction of the azide group and subsequent protection–deprotection transformations. The chemical reactivity of the aminoalditol was tested in the reductive amination reaction with a selectively protected sucrose monoaldehyde. Keywords

• in diol 2 is not possible. Thus we decided to differentiate the terminal positions in the stage of higher sugar 1. The replacement of the hydroxy group at the C12-position with an azide, accomplished successfully under Mistunobu conditions, afforded azide 4 in 95% yield (Scheme 1). The crucial step

• was the liberation of the anomeric position (C1), which, as we noticed, can cause problems. We subjected azide 4 to acetolysis and, although this reaction is very capricious in higher sugar chemistry [7][8], succeeded in the preparation of the desired hemiacetal acetate 5 in very good yield (86%) as a

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• size of the macrocycle formed during the glycosylation (Scheme 12) [80][81]. Thioglycoside donor 45 containing a 2-O-propargyl group and acceptor 46 with an azide-containing protecting group were connected using a click reaction to afford the tethered intermediate 47. Upon treatment with NIS/TfOH

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• triazole moiety (Scheme 37a) using benzyl halides, sodium azide and a terminal alkyne via an alumina-supported copper catalyst. Using 10 mol % of Cu/Al2O3, differently substituted phenyl acetylenes and aliphatic alkynes led to 70–96% yield of triazoles [152]. Phenyl boronic acids were also used to

• (Scheme 38). The same method was easily applicable to the synthesis using alkyl azide in 15 min [155]. Among various synthetic routes of indoles synthesis, Larock method [156] possibly be the important one which utilizes 2-alkynylaniline as intermediate towards intra-molecular cyclization. Stolle and co

Influence of the milling parameters on the nucleophilic substitution reaction of activated β-cyclodextrins

• László Jicsinszky,
• Kata Tuza,
• Giancarlo Cravotto,
• Andrea Porcheddu,
• Francesco Delogu and
• Evelina Colacino

Beilstein J. Org. Chem. 2017, 13, 1893–1899, doi:10.3762/bjoc.13.184

• contact between balls. Unlike the reactivity in solution, under mechanochemical conditions the sulfur nucleophile (thiourea, TU) was less effective than the azide ion in the substitution reaction. A similar reversal of reactivity has been already observed for halogens [12][13][28]. The experimental

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• directed mutagenesis of the potent residues [64]. In these cases, the mutated enzymes are no longer able to perform the hydrolysis of the substrates. The use of external and suitable nucleophilic anions such as azide, formate or acetate allows the rescue of the activity and can also represent an efficient

• are named thioligases [65]. Based on the mechanism, here the formation of the glycosyl–enzyme intermediate requires the use of an activated glycosyl donor, such as dinitrophenyl or azide glycosides, and the glycosylation step needs stronger nucleophiles such as thiol derivatives. The choice of the