Solid-phase enrichment and analysis of electrophilic natural products

• Frank Wesche,
• Yue He and
• Helge B. Bode

Beilstein J. Org. Chem. 2017, 13, 405–409, doi:10.3762/bjoc.13.43

• entomopathogenic Photorhabdus bacteria. Keywords: azides; click chemistry; enrichment; electrophilic natural products; epoxides; glidobactin; Photorhabdus; stilbenes; Introduction Microorganisms are a major source for novel natural products and the subsequent development of new drugs for all kinds of

• dehydroalanine [6][7], ketones, aldehydes [8][9], carboxylic acids [8][9], amines [8][9][10], thiols [8][9], alcohols [11], epoxides [12], terminal alkynes [13][14] and azides [15] can be targeted to introduce a label. Such labels might increase the visibility in UV or MS detection in liquid chromatography

• ), Scheme 1) is such a resin able to react with a broad range of azides [15]. Thus, the metabolic fate of azide-containing biosynthesis intermediates or building blocks can be studied and natural products containing these azides can be identified. Herein we describe the application of the CARR enrichment

A postsynthetically 2’-“clickable” uridine with arabino configuration and its application for fluorescent labeling and imaging of DNA

• Heidi-Kristin Walter,
• Bettina Olshausen,
• Ute Schepers and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2017, 13, 127–137, doi:10.3762/bjoc.13.16

• cells. Keywords: dyes; fluorescence; nucleic acid; oligonucleotide; Introduction The “click”-type reactions [1], in particular the 1,3-dipolar cycloaddition between alkynes and azides (CuAAC) is a broadly applied strategy for postsynthetic oligonucleotide modification since both reactive groups are

• cannot only be applied for conventional postsynthetic oligonucleotide modification in solution but also on solid phase [11] and for the introduction of multiple postsynthetic modifications [12]. The azide groups for CuAAC are typically placed onto the fluorescent dyes since azides are not compatible with

• donors in the energy transfer-based DNA systems (vide infra). The corresponding dye azides were synthesized as previously described [19][23][24]. The modified double strands (ds) DNA2aD1 to DNA2aD4 were compared with their structural counterpart among the duplexes DNA2rD1 to DNA2rD4 with respect to their

Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

• materials can be used in the extruder, through the use of s-Buli by Höcker et al., reagents that are potentially explosive or can be ignited when dry or exposed to friction are too hazardous to be used in an extrusion process, therefore chemistry involving azides or hydrazines for example, would need to be

Versatile synthesis of end-reactive polyrotaxanes applicable to fabrication of supramolecular biomaterials

• Atsushi Tamura,
• Asato Tonegawa,
• Yoshinori Arisaka and
• Nobuhiko Yui

Beilstein J. Org. Chem. 2016, 12, 2883–2892, doi:10.3762/bjoc.12.287

• ][17][18][19][20][21], few have reported on the synthesis of PRXs bearing terminal azides or alkynes [22][23]. This is probably because of the difficulties in synthesizing sufficient amounts of bulky stopper molecules containing azide or alkynyl groups for the capping reaction. Herein, we describe a

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• substantial dipole moment (≈4.5 D) almost aligned with the C5–H bond and the relatively high acidity of this position (pKa(DMSO) = 27–28, for the 1H-tautomer). These heterocycles, which are easily available from 1,3-cycloaddition of alkynes and azides, can both form strong C–H bonds with hydrogen bond

Catalytic Wittig and aza-Wittig reactions

• Zhiqi Lao and
• Patrick H. Toy

Beilstein J. Org. Chem. 2016, 12, 2577–2587, doi:10.3762/bjoc.12.253

• catalytic aza-Wittig reactions (Scheme 16) [33]. It was reported that mixing 2-aminobenzoyl azides 55, carboxylic acids 56, isocyanides 57 with aldehydes 6 in methanol generated intermediates 58, which underwent rearrangement to isocyanates 59 in refluxing toluene. Finally, catalytic aza-Wittig reactions

• with 44 produced cyclized final products 54 via iminophosphoranes 60. Phosphine-catalyzed reactions The initial research in this area was performed by Floris L. van Delft and co-workers who reported the synthesis of 61 and its use in catalytic Staudinger reactions for the reduction of azides 62 to

• addition to phosphine oxide-catalyzed aza-Wittig reactions, Ding’s research group has also explored the use of phosphine catalysis in such reactions. In their initial report regarding this strategy, they used 1 to catalyze intramolecular reactions that converted aryl azides 68 into 4(3H)-quinazolinones 69

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• radioactive peaks on a radio-TLC using a radio-TLC scanner (Fuji, BAS2000). [18F]Fluoride was produced using the PET cyclotron Cyclone 18/9 (IBA). [18O]H2O was irradiated with protons (18 MeV, 30 µA) exploiting the 18O(p,n)18F nuclear reaction. CAUTION! Hazard warning for organic azides: risk of explosion by

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

• Ilya V. Efimov,
• Marsel Z. Shafikov,
• Nikolai A. Beliaev,
• Natalia N. Volkova,
• Tetyana V. Beryozkina,
• Wim Dehaen,
• Zhijin Fan,
• Viktoria V. Grishko,
• Gert Lubec,
• Pavel A. Slepukhin and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2016, 12, 2390–2401, doi:10.3762/bjoc.12.233

• with inverse electron demand, similarly to the reaction of enamines with azides [37]. To gain deeper insights into the mechanism of the cycloaddition between nitrile oxides and enamines, quantum chemical calculations were carried out using the Gaussian 09 [38] programs package at B3LYP/def2-TZVP [39

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• particularly efficient when good nucleophiles, such as sulfur-containing reactants or inorganic azides, were used. The aim of our study is to highlight the use of HEBM in the preparation of a number of practically important CD derivatives, as seen in Scheme 1. Although in our work neither the reaction

• enough to warm the reaction mixture to an appropriate value. The very low solubility of the CD azides created an additional disadvantage and so we discarded the use of these wetting solvents. Alternatively, a wetting substance, which is an equally poor solvent for the CD derivatives and NaI, 1-pentanol

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• 46% yield over twelve steps (Scheme 4). Azide 34 was easily converted to amino azide 36 via a two-step sequence, but conversion of azide 34 to amino azide 37 was more complex and required additional transformations [56]. Conversion of both amino azides 36 and 37 to azido acids 38 and 39 began with

• protecting group manipulation and installation of the guanidine using S-methylisothiourea 33 (Scheme 5). Mitsunobu cyclisation followed by deprotection and oxidation afforded the azido acids 38 and 39 in 40% yield over 8 steps from amino azides 36 and 37. Synthesis of β-hydroxyenduracididine by Nieuwenhze et

Stereoselective synthesis of fused tetrahydroquinazolines through one-pot double [3 + 2] dipolar cycloadditions followed by [5 + 1] annulation

• Xiaofeng Zhang,
• Kenny Pham,
• Shuai Liu,
• Marc Legris,
• Alex Muthengi,
• Jerry P. Jasinski and
• Wei Zhang

Beilstein J. Org. Chem. 2016, 12, 2204–2210, doi:10.3762/bjoc.12.211

• addition to formaldehyde, other aldehydes could also be used for the [5 + 1] annulation according to literature [34][35]. Conclusion A one-pot reaction sequence involving [3 + 2] cycloaddition of azomethine ylides, [3 + 2] cycloaddition of azides with alkenes, and denitrogenation followed by a [5 + 1

Application of Cu(I)-catalyzed azide–alkyne cycloaddition for the design and synthesis of sequence specific probes targeting double-stranded DNA

• Svetlana V. Vasilyeva,
• Vyacheslav V. Filichev and
• Alexandre S. Boutorine

Beilstein J. Org. Chem. 2016, 12, 1348–1360, doi:10.3762/bjoc.12.128

• synthesis of conjugates of pyrrole–imidazole polyamide minor groove binders (MGB) with fluorophores and with triplex-forming oligonucleotides (TFOs). Diverse bifunctional linkers were synthesized and used for the insertion of terminal azides or alkynes into TFOs and MGBs. The formation of stable triple

Copper-catalyzed [3 + 2] cycloaddition of (phenylethynyl)di-p-tolylstibane with organic azides

• Mizuki Yamada,
• Mio Matsumura,
• Yuki Uchida,
• Masatoshi Kawahata,
• Yuki Murata,
• Naoki Kakusawa,
• Kentaro Yamaguchi and
• Shuji Yasuike

Beilstein J. Org. Chem. 2016, 12, 1309–1313, doi:10.3762/bjoc.12.123

• ] cycloaddition of a ethynylstibane with organic azides in the presence of CuBr (5 mol %) under aerobic conditions. The reaction of 5-stibanotriazole with HCl, I2, and NOBF4 afforded 1-benzyl-4-phenyltriazole, 1-benzyl-5-iodo-4-phenyltriazole, and a pentavalent organoantimony compound, respectively. Keywords

• alkyne, an organic azide, and an H-phosphate in the presence of CuCl2 (10 mol %) and triethylamine (2 equiv) afforded the desired 1,2,3-triazolyl-5-phosphonates [23]. Fokin et al. carried out the reaction of ethynylbismuthane with organic azides using CuOTf (5 mol %) and isolated 5-bismuthano-1,2,3

• been no reports concerning the synthesis of 1,4,5-trisubstituted 5-stibano-1,2,3-triazoles. Herein, we report a novel CuAAC of a simple alkynylstibane, (phenylethynyl)di-p-tolylstibane, with organic azides to form fully substituted 5-organostibano-1,2,3-triazoles. Results and Discussion We initially

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• process involves the 1,3-dipolar cycloaddition of alkynes 182 with in situ generated nitrone 185 to afford isoxazolines 186 which rapidly rearrange to aziridinylphosphonates 183. An efficient method for the synthesis of 1,2,3-triazoles is the copper(I)-catalyzed Husigen cycloaddition of azides with

• alkynes. Based on this method, Li et al. have developed a copper(I)-catalyzed three-component reaction between alkynes 187, azides 188 and dialkyl phosphonates 189 to give 1,2,3-triazolyl-5-phosphonates 190 (Scheme 40) [78]. The desired products were obtained in 62–88% yield under optimized conditions

Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N–O bond-forming cyclization of 2-azidobenzoic acids

• Daria Yu. Dzhons and
• Andrei V. Budruev

Beilstein J. Org. Chem. 2016, 12, 874–881, doi:10.3762/bjoc.12.86

• 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions. Keywords: aryl azides; azepinones; 2,1

• nitro compounds [17][18][19][20][21], two other routes are available: the annulation of nitroso compounds [22][23] and the thermal [24], catalytic [25][26][27] or photochemical cyclization of aryl azides [28][29][30][31]. However, the presence of electron-withdrawing substituents in the 3-, 5- and 7

• -azepines 3 as products of the photolysis or thermolysis of aromatic azides [34][35]. The proposed mechanism for their formation was confirmed by identification of the reaction intermediates using low-temperature and time-resolved spectroscopy [36][37][38][39][40][41][42][43]. It is currently believed that

Bi- and trinuclear copper(I) complexes of 1,2,3-triazole-tethered NHC ligands: synthesis, structure, and catalytic properties

• Shaojin Gu,
• Jiehao Du,
• Jingjing Huang,
• Huan Xia,
• Ling Yang,
• Weilin Xu and
• Chunxin Lu

Beilstein J. Org. Chem. 2016, 12, 863–873, doi:10.3762/bjoc.12.85

• yield (Table 1, entry 4). However, only a moderate yield was obtained when a CH3CN/H2O solvent mixture was used (Table 1, entry 6). Thus, CH3CN was selected as the optimal solvent. Having optimized the reaction conditions, we extended the CuAAC reaction to other azides and alkynes at room temperature in

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• blocks in synthetic organic chemistry. Recently, they have attracted also strong interest for applications in materials science and chemical biology [1]. One of the most important transformations of alkynes is the copper-catalyzed [3 + 2] cycloaddition with azides, which can be performed under mild

• modified reaction conditions (10 mol % AuCl(SMe2), three equivalents TIPS-EBX (1a) and 2 mol % trifluoroacetic acid as co-catalyst) [39]. They also demonstrated that the obtained silylalkyne products can be easily deprotected with fluoride sources to allow bioconjugation via cycloaddition with azides

Synthesis of bi- and bis-1,2,3-triazoles by copper-catalyzed Huisgen cycloaddition: A family of valuable products by click chemistry

• Zhan-Jiang Zheng,
• Ding Wang,
• Zheng Xu and
• Li-Wen Xu

Beilstein J. Org. Chem. 2015, 11, 2557–2576, doi:10.3762/bjoc.11.276

• coupling; Introduction Since its discovery by Huigsen and co-workers fifty years ago [1][2][3][4], the Huisgen cycloaddition of azides to alkynes has gained much attention due to its potential to yield a wide variety of triazoles with structurally diverse and functionalized groups, especially with respect

• from a double CuAAC reaction between various sources of 1,3-butadiynes with the substituted azides. In general, two different methods have been developed for the construction of the 4,4'-bitriazoles: (1) The one-pot double CuAAC reaction of 1,3-butadiyne with azides. (2) Two successive CuAAC reactions

• with different or same azides that require the deprotection of the second reactive site to liberate another alkyne moiety. In 2007, Monkowius et al. reported that the 4,4'-bitriazoles 3 could be synthesized by the two-fold click reaction between 1,3-butadiyne and substituted organic azides [17], and

Synthesis of D-fructose-derived spirocyclic 2-substituted-2-oxazoline ribosides

• Madhuri Vangala and
• Ganesh P. Shinde

Beilstein J. Org. Chem. 2015, 11, 2289–2296, doi:10.3762/bjoc.11.249

• glycosyl azides via intramolecular condensation with a vicinal ester group in the presence of triphenylphosphine [27] or from the reaction of D-glucals with N-iodosuccinimide and amides [28][29]. Alternatively, 5 can be derived by a Ritter-like [30][31] transformation, involving trapping of the

Effective ascorbate-free and photolatent click reactions in water using a photoreducible copper(II)-ethylenediamine precatalyst

• Redouane Beniazza,
• Natalia Bayo,
• Florian Molton,
• Carole Duboc,
• Stéphane Massip,
• Nathan McClenaghan,
• Dominique Lastécouères and
• Jean-Marc Vincent

Beilstein J. Org. Chem. 2015, 11, 1950–1959, doi:10.3762/bjoc.11.211

• photoreduced in water when alkynes were present in solution. The catalytic activity of 1 for click reactions involving a range of water-soluble alkynes and azides, in particular saccharides, was tested under various illumination conditions. Complex 1 was found to exhibit a photolatent character, the

• when exposed to TLC lamp. Having established the most efficient illumination conditions, reactions were conducted on a range of water-soluble alkynes and azides by irradiating the NMR tubes with the TLC lamp for 1 h and then leaving it under ambient light. As seen in Scheme 4, a variety of triazoles 9

• spectroscopy, that the alkynes can serve as effective and practical electron source to allow the reduction in a light-dependent process photosensitized by the benzophenone. Complex 1 proved to be an effective photolatent catalyst for reactions conducted in water involving water-soluble alkynes and azides

Synthesis of quinoline-3-carboxylates by a Rh(II)-catalyzed cyclopropanation-ring expansion reaction of indoles with halodiazoacetates

• Magnus Mortén,
• Martin Hennum and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2015, 11, 1944–1949, doi:10.3762/bjoc.11.210

• -caboxylates we obtained by using our method (Table 1) compares favorably with three recently published methods where arylmethyl azides [22], arylallyl azides [23] and o-nitrobenzaldehydes [24] were used as starting materials. The mechanism of heterocyclic ring expansions has briefly been studied for thermal

Reaction of allene esters with Selectfluor/TMSX (X = I, Br, Cl) and Selectfluor/NH₄SCN: Competing oxidative/electrophilic dihalogenation and nucleophilic/conjugate addition

• A. Srinivas Reddy and
• Kenneth K. Laali

Beilstein J. Org. Chem. 2015, 11, 1641–1648, doi:10.3762/bjoc.11.180

• presence of phosphane catalysts an umpolung addition takes place, whereby the nucleophilic addition occurs inversely at the beta-gamma double bond [22][23]. Vinyl azides have been prepared by hydroazidation of allenyl esters through a Michael-type addition with high regio- and stereoselectivity [24

Synthesis of alpha-tetrasubstituted triazoles by copper-catalyzed silyl deprotection/azide cycloaddition

• Zachary L. Palchak,
• Paula T. Nguyen and
• Catharine H. Larsen

Beilstein J. Org. Chem. 2015, 11, 1425–1433, doi:10.3762/bjoc.11.154

• second portion of the sequence in Scheme 1: a tandem deprotection–cycloaddition of tetrasubstituted TIPS-protected propargylamines 4 that would allow them to react in situ with various azides 5 to give hindered triazoles 6. As a copper(I) catalyst is required for azide–alkyne cycloaddition, the

• . Alternate organic azides were synthesized according to known methods [39][40][41]. 4-Methylbenzyl azide forms triazole 6g in a comparable yield to 6a, but electron-poor 4-(trifluoromethyl)benzyl azide forms triazole 6h in lower yield. Aryl and alkyl azides display parallel reactivity in the formation of

• /cycloaddition. Tetrasubstituted silylpropargylamines form hindered triazole products. Assorted azides for formation of alpha-tetrasubstituted triazoles. Supporting Information The Supporting Information features experimental details, compound characterization, and copies of 1H and 13C NMR spectra of triazoles

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• 9H-fluorene (298) and propargyl bromide, which on further treatment with 1,4-diazidobutane (300) and xylyl azides 302a–c in the presence of CuSO4·5H2O and sodium ascorbate in THF/water (1:1) gave the corresponding macrocycles (301, 42%) and (303a–c, 60–70% yield, Scheme 52). Murphy and Leyden [186

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• inventory of the reactive intermediate reduced the safety concerns associated with the use of the azide. The choice of flow when handling hazardous materials like azides is a very frequently encountered driver and several publications detailing the associated benefits have emerged over the years [88][89][90