Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

• Eric Buchy,
• Branko Vukosavljevic,
• Maike Windbergs,
• Dunja Sobot,
• Camille Dejean,
• Simona Mura,
• Patrick Couvreur and
• Didier Desmaële

Beilstein J. Org. Chem. 2016, 12, 1127–1135, doi:10.3762/bjoc.12.109

• -bromopropane-d7 (8) with triphenylphosphine [29]. To our surprise, condensation of dialdehyde 5 with one equivalent of the ylide 4 (9, n-BuLi, THF, −78 °C) did not afford any amount of the desired deuterated olefin but only polar material that could not be characterized. In an attempt to find more efficient

• reaction conditions, we investigated this reaction using the simple aldehyde 10 as a model compound, easily accessible from squalene according to the van Tamelen procedure [30]. The condensation of ylide 4 with 10 seemed to be an easy task, but many well-established procedures using various bases (n-BuLi

• , LiHMDS, NaH/DMSO, PhLi) [29][31][32] gave only intractable materials. We finally found that the treatment of 10 with the “instant ylide mixture” of Schlosser made by grinding a solid mixture of 9 and NaNH2 [33] delivered the desired squalene-d6 (11) although in a low 18% yield. However, when applied to

Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(−)-myrtenol nitrate

• Sean P. Bew,
• Glyn D. Hiatt-Gipson,
• Graham P. Mills and
• Claire E. Reeves

Beilstein J. Org. Chem. 2016, 12, 1081–1095, doi:10.3762/bjoc.12.103

• , the synthesis of either (E)-3-methyl-4-chlorobut-2-en-1-ol ((E)-60) or (Z)-3-methyl-4-chlorobut-2-en-1-ol ((Z)-61, Scheme 8). Reacting triphenylphosphine with 1-((2-bromoethoxy)methyl)-4-methoxybenzene (55) generated non-stabilized phosphonium ylide (2-(4-methoxybenzyloxy)ethyl)triphenylphosphonium

• ester via a Horner–Wadsworth–Emmons reaction caught our attention [47]. Changing tack and in a slightly modified procedure to that originally reported by Fujiwara et al. triethyl phosphonoacetate was deprotonated (NaH) and the resulting stabilised ylide (not shown) reacted by slow addition of

• of mercury(I) chloride (0.06 mol %) and sulfuric acid (0.35 mol %) in water following the procedure of Boger et al. [51]. 63 was afforded in an unoptimized 78% yield. Employing the conditions outlined in Scheme 10 63 reacted with the stabilized ylide generated from the deprotonation of triethyl

One-pot synthesis of enantiomerically pure N-protected allylic amines from N-protected α-amino esters

• Gastón Silveira-Dorta,
• Sergio J. Álvarez-Méndez,
• Víctor S. Martín and
• José M. Padrón

Beilstein J. Org. Chem. 2016, 12, 957–962, doi:10.3762/bjoc.12.94

• ]. However, that preliminary study was limited to the use of phosphonium ylide reagents and commonly t-Boc (iBoc and Ac were used once) as N-protecting group. To the best of our knowledge, no further studies on the reaction conditions have been carried out. Instead, the method was applied to N-Ac aspartic

• Discussion The experimental procedure for the tandem reduction–Wittig olefination synthesis of allylic amines reported the use of toluene as solvent for the reduction step and THF as solvent to prepare the phosphonium ylide [17]. Consequently, the Wittig olefination takes place in a 2:1 (toluene/THF) solvent

• as starting material (S)-methyl 2-(dibenzylamino)propanoate (1) [22]. In order to avoid the stereochemical drawback of the Wittig olefination (i.e., mixture of E and Z isomers), we selected the stabilized ylide ethyl 2-(triphenylphosphoranylidene)acetate, which gives the E isomer [23]. The results

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• (Table 3) [9]. This work is particularly important because, at that time, the carbenoids derived from rhodium complexes were the most used for insertion reactions in C(sp3)–H bonds. Comparing the results of Table 3, the same enantiomer was obtained mainly for both carbenoid precursors, ylide 42a and the

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• muraymycin core structure (Scheme 6) [78][99]. The key step of their route was a sulfur-ylide reaction with high substrate-controlled diastereoselectivity [100][101][102]. This epoxide-forming sulfur-ylide reaction had been established before by Sarabia et al. [103][104]. After some initial confusion

Strecker degradation of amino acids promoted by a camphor-derived sulfonamide

• M. Fernanda N. N. Carvalho,
• M. João Ferreira,
• Ana S. O. Knittel,
• Maria da Conceição Oliveira,
• João Costa Pessoa,
• Rudolf Herrmann and
• Gabriele Wagner

Beilstein J. Org. Chem. 2016, 12, 732–744, doi:10.3762/bjoc.12.73

• compensated in the products 7a, 7b and 8, respectively (Figure 7). A mechanism of the type 5 → 7 (azomethine ylide route) has been proposed for the ninhydrin reaction [30] and other Strecker-type degradation processes [31]. Oxazolidin-5-ones were shown by IR spectroscopy to be formed from amino acids and

• ) via the transition state glyoxal/glycine, CO2 loss. Supporting Information File 89: Calculated reaction (IRC path) via the transition state imine ninhydrine/glycine, zwitterion, azomethine ylide formation. Supporting Information File 90: Calculated reaction (IRC path) via the transition state imine

Diradical reaction mechanisms in [3 + 2]-cycloadditions of hetaryl thioketones with alkyl- or trimethylsilyl-substituted diazomethanes

• Grzegorz Mlostoń,
• Paulina Pipiak and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2016, 12, 716–724, doi:10.3762/bjoc.12.71

• -thiadiazoline 2a can be subsequently used as a precursor of the reactive thiobenzophenone S-methanide (a thiocarbonyl ylide) 3a at ca. −45 °C, when the evolution of N2 takes place [16][17][18][19][20]. An analogous course of the reaction with diazomethane was observed in the case of thiofluorenone (1b, Scheme 1

• thiocarbonyl ylide and its reaction with another molecule of 1a were competitive pathways. Finally, the reactions of 7c with symmetrically substituted dihetaryl thioketones 1d and 1e were performed at −75 °C, and in both cases, the sterically crowded 4,4,5,5-tetrahetaryl-1,3-dithiolanes 10r and 10s

• . Only after warming up above −45/40 °C compounds 2 are expected to decompose yielding the reactive thiocarbonyl ylide 3. Under these conditions, the latter intermediates can undergo either 1,3-dipolar electrocyclization to give thiiranes 8 or dimerization leading to 1,4-dithianes 4 [20][26]. This

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• , organocatalyst 23. More specifically, the reaction is a catalytic asymmetric synthesis of 8-oxabicyclooctanes via an intermolecular [5 + 2] pyrylium cycloaddition (Scheme 9) [20]. This novel [5 + 2] cycloaddition describes the coupling of a pyrylium ylide 19 with dipolarophile 20, in order to give access to the

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• nucleophile and then as a leaving group in cyanide-catalysed benzoin reactions [8]. Analogously, Breslow invoked the generation of a nucleophilic thiazolylidene species 1 via deprotonation of the thiazolium salt by base. The ylide 1 may also be represented as its resonance structure 1’ (carbene). Nucleophilic

Hydroquinone–pyrrole dyads with varied linkers

• Hao Huang,
• Christoffer Karlsson,
• Maria Strømme,
• Martin Sjödin and
• Adolf Gogoll

Beilstein J. Org. Chem. 2016, 12, 89–96, doi:10.3762/bjoc.12.10

• work-up involved simple filtration and washing with toluene. Use of t-BuOK as a base to deprotonate the phosphonium salt resulted in a dark red phosphorous ylide, to which 1-(triisopropylsilyl)-1H-pyrrole-3-carbaldehyde was added, followed by heating at 80 °C. The desired product 4c was obtained in 40

Direct estimate of the internal π-donation to the carbene centre within N-heterocyclic carbenes and related molecules

• Diego M. Andrada,
• Nicole Holzmann,
• Thomas Hamadi and
• Gernot Frenking

Beilstein J. Org. Chem. 2015, 11, 2727–2736, doi:10.3762/bjoc.11.294

• calculations and with an energy decomposition analysis. The investigated molecules include N-heterocyclic carbenes (NHCs), the cyclic alkyl(amino)carbene (cAAC), mesoionic carbenes and ylide-stabilized carbenes. The bonding analysis suggests that the carbene centre in cAAC and in diamidocarbene have the

• size of the backbone ring [39][40][41], variation of the α-heteroatoms [7], anti-Bredt NHCs [42][43], mesoionic NHCs [44][45][46][47], ylide stabilized carbenes [48][49][50][51] and other [52][53][54][55]. A remarkable variation was introduced with the cyclic alkyl(amino)carbene (cAAC) by Bertrand in

• mesoionic carbenes for which no resonance form without formal charges can be written [73]. Molecules 11 and 12 are NHCs with one nitrogen donor atom where the carbene centre is additionally stabilised by another hetero π-donor. Compounds 13 and 14 are ylide-stabilised carbenes while 15 is a diamidocarbene

Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

• Jingjing Wang,
• Samuel Z. Y. Ting and
• Joanne E. Harvey

Beilstein J. Org. Chem. 2015, 11, 1815–1822, doi:10.3762/bjoc.11.197

• Jingjing Wang Samuel Z. Y. Ting Joanne E. Harvey Centre for Biodiscovery, School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington 6140, New Zealand 10.3762/bjoc.11.197 Abstract Bestmann ylide [(triphenylphosphoranylidene)ketene] acts as a chemical

• linchpin that links nucleophilic entities, such as alcohols or amines, with carbonyl moieties to produce unsaturated esters and amides, respectively. In this work, the formation of α,β,γ,δ-unsaturated esters (dienoates) is achieved through the coupling of Bestmann ylide, an alcohol and an α,β-unsaturated

• products zampanolide and dactylolide is investigated using Bestmann ylide to link the C16–C20 alcohol with the C3–C8 aldehyde fragment. Keywords: Bestmann ylide; dactylolide; dienoate; (triphenylphosphoranylidene)ketene; zampanolide; Introduction (Triphenylphosphoranylidene)ketene, Ph3P=C=C=O (1), was

Fe(II)/Et₃N-Relay-catalyzed domino reaction of isoxazoles with imidazolium salts in the synthesis of methyl 4-imidazolylpyrrole-2-carboxylates, its ylide and betaine derivatives

• Ekaterina E. Galenko,
• Olesya A. Tomashenko,
• Alexander F. Khlebnikov,
• Mikhail S. Novikov and
• Taras L. Panikorovskii

Beilstein J. Org. Chem. 2015, 11, 1732–1740, doi:10.3762/bjoc.11.189

• according to Scheme 2, whereby excluding the isolation of often unstable 2H-azirines [34]. Results and Discussion The synthetic scheme (Scheme 2) implies an implementation of all stages (1: generation of azirine 8 from isoxazole 7 under FeCl2 catalysis; 2: formation of phenacylimidazolium ylide 10 induced

• by Et3N; 3: activation of azirine 8 with Et3HN+Br−; 4: reaction of the activated azirine 11 with the imidazolium ylide 10) as a domino reaction under relay catalysis [35][36]. A simple procedure, consisting of stirring a mixture of isoxazole 7, phenacylimidazolium salt 9, FeCl2·4H2O and Et3N in MeCN

• hydrolyzing the ester group. Ylides 2 can also be debenzylated, affording the corresponding pyrrolyl imidazoles 12. Thus, ylide 2h was debenzylated on Pd/C with hydrogen to produce methyl 5-(4-fluorophenyl)-4-(1H-imidazol-1-yl)-3-phenyl-1H-pyrrole-2-carboxylate (12d) in quantitive yield. As mentioned above

Ruthenium indenylidene “1^st generation” olefin metathesis catalysts containing triisopropyl phosphite

• Stefano Guidone,
• Fady Nahra,
• Alexandra M. Z. Slawin and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2015, 11, 1520–1527, doi:10.3762/bjoc.11.166

• in vacuo. The crude product was recrystallized from dichloromethane/pentane. The solid was collected by filtration and washed with pentane (3 × 3 mL). The product was obtained as a brownish green solid in a mixture with the phosphonium ylide 3 (0.032 g, 35%). 1H NMR of the mixture (400 MHz, CD2Cl2) δ

• ruthenium complexes used in olefin metathesis reactions. Molecular structure of mixed phosphine/phosphite complex 1. Hydrogen atoms are omitted for clarity. Molecular structure of 2 and the ylide 3. Hydrogen atoms and solvent molecules are omitted for clarity. Selected bond distances (Å) and angles (°) (ESD

Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes

• Luke J. O’Driscoll,
• Sissel S. Andersen,
• Marta V. Solano,
• Dan Bendixen,
• Morten Jensen,
• Troels Duedal,
• Jess Lycoops,
• Cornelia van der Pol,
• Rebecca E. Sørensen,
• Karina R. Larsen,
• Kenneth Myntman,
• Christian Henriksen,
• Stinne W. Hansen and
• Jan O. Jeppesen

Beilstein J. Org. Chem. 2015, 11, 1112–1122, doi:10.3762/bjoc.11.125

• -thiones 19 [38]. These reactions (Scheme 3 and Table 1) use an excess of 19 to minimise the formation of 5a as a byproduct, making it possible to isolate tosylated MPTTFs (such as 4a–f) in high yields. This is believed to be due to the higher reactivity of sulfur ylide intermediates (formed from 1,3

Indolizines and pyrrolo[1,2-c]pyrimidines decorated with a pyrimidine and a pyridine unit respectively

• Marcel Mirel Popa,
• Emilian Georgescu,
• Mino R. Caira,
• Florentina Georgescu,
• Constantin Draghici,
• Raluca Stan,
• Calin Deleanu and
• Florea Dumitrascu

Beilstein J. Org. Chem. 2015, 11, 1079–1088, doi:10.3762/bjoc.11.121

• structures of two of the starting materials, 4-(2-pyridyl)pyrimidine and 4-(4-pyridyl)pyrimidine, are also reported. Keywords: indolizine; nitrogen heterocycles; N-ylide; 4-pyridylpyrimidine; pyrrolo[1,2-c]pyrimidine; Introduction Two heteroarenes linked through a single bond [1] proved to be versatile

• 17 on the oxirane ring in the 1,2-epoxybutane (Scheme 4). The reactive intermediate obtained by the ring opening of the 1,2-epoxybutane abstracts a methylene proton from the salt, generating the corresponding N-ylide (18) in situ. The N-ylide reacts further with the acetylenic dipolarophile to give a

On the strong difference in reactivity of acyclic and cyclic diazodiketones with thioketones: experimental results and quantum-chemical interpretation

• Andrey S. Mereshchenko,
• Alexey V. Ivanov,
• Viktor I. Baranovskii,
• Grzegorz Mloston,
• Ludmila L. Rodina and
• Valerij A. Nikolaev

Beilstein J. Org. Chem. 2015, 11, 504–513, doi:10.3762/bjoc.11.57

• bond (step 1), followed by decomposition of thiadiazoline 6 formed (step 2) and competitive electrocyclization of the intermediate thiocarbonyl ylide 7 either into 1,3-oxathiole 3 or thiirane 4 (step 3) (Scheme 2). According to the latest molecular orbital (MO) theory, reactions of diazodicarbonyl

• ) demonstrate that formation of thiadiazolines 6 from 1a–d and 2a is thermodynamically unfavorable. However, the total value of the Gibbs free energy change for the formation of molecular nitrogen and thiocarbonyl ylide 7 from 1a–d and 2a, ΔG1–7 = ΔG1 + ΔG2, is negative. Therefore, the formation of the

• , the first step of the process (cycloaddition) must be a rate-determining step, and therefore, the larger value of ΔG1# corresponds to the slower formation of thiocarbonyl ylide 7. IRC scans have demonstrated that diazo compounds 1 and thiobenzophenone (2a) are smoothly converted to thiadiazolines 6

Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo

• Alireza Shakoori,
• John B. Bremner,
• Mohammed K. Abdel-Hamid,
• Anthony C. Willis,
• Rachada Haritakun and
• Paul A. Keller

Beilstein J. Org. Chem. 2015, 11, 481–492, doi:10.3762/bjoc.11.54

• derivatives 12–16 was previously reported [4]. Scheme 6 illustrates a tentative proposed mechanism for the synthesis of the azepinodiindolones and the red diindolone heterocycles through an intermediatory diallylindigo 24 (Scheme 6). Deprotonation could then produce a stabilised ylide, thus providing a formal

Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: three-membered ring opening vs 1,5-cyclization

• Nikolai V. Rostovskii,
• Mikhail S. Novikov,
• Alexander F. Khlebnikov,
• Galina L. Starova and
• Margarita S. Avdontseva

Beilstein J. Org. Chem. 2015, 11, 302–312, doi:10.3762/bjoc.11.35

• involves the 1,5-cyclization of azirinium ylide 9f–h to dihydroazireno[2,1-b]oxazole 10f–h followed by cycloaddition of the latter to ketene 12 to give two regioisomeric adducts 6f,g and 7f–h (Scheme 3). Several examples of the 1,5-cyclization of azomethine ylides bearing an α-keto group into oxazole

• derivatives were reported [27][28][29]. As also known, the azomethine ylide derived from N-benzylideneanisidine and diazoacetylacetone under Rh2(OAc)4-catalysis undergoes 1,3-cyclization to an aziridine derivative in high yield, rather than 1,5-cyclization [22]. However, no cyclizations of azirinium ylides

• the model azirinium ylide 9j: ring opening into azadiene 3j and 1,5-cyclization into azirenooxazole 10j (Scheme 4), by means of DFT calculations (B3LYP/6-31+G(d,p)). In addition, two reasonable pathways for the formation of adducts 6j and 7j formed from azirenooxazole 10j and ketene 12 were studied at

Switching the reaction pathways of electrochemically generated β-haloalkoxysulfonium ions – synthesis of halohydrins and epoxides

• Akihiro Shimizu,
• Ryutaro Hayashi,
• Yosuke Ashikari,
• Toshiki Nokami and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2015, 11, 242–248, doi:10.3762/bjoc.11.27

• part of the resulting sulfur ylide abstracts a proton attached to the carbon adjacent to the oxygen to give α-bromoketone 4a-Br by the Swern–Moffatt-type oxidation mechanism [23][24][25][26][27]. On the other hand, the hydroxide ion attacks the sulfur atom in 3a-Br and cleaves the S–O bond to give the

New highlights of the syntheses of pyrrolo[1,2-a]quinoxalin-4-ones

• Emilian Georgescu,
• Alina Nicolescu,
• Florentina Georgescu,
• Florina Teodorescu,
• Daniela Marinescu,
• Ana-Maria Macsim and
• Calin Deleanu

Beilstein J. Org. Chem. 2014, 10, 2377–2387, doi:10.3762/bjoc.10.248

• opening and generation of the benzimidazolium N-ylide 7 by the action of the alkoxide. The benzimidazolium N-ylide 7 reacts with the activated alkynes 3 to give the corresponding primary cycloadduct dihydropyrrolo[1,2-a]benzimidazoles 8. The formation of pyrrolo[1,2-a]quinoxalin-4-ones 4 involves the

Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines via silver triflate-catalyzed or electrophile-mediated one-pot tandem reaction

• Xiaoli Zhou,
• Meiling Liu,
• Puying Luo,
• Yingjun Lai,
• Tangtao Yang and
• Qiuping Ding

Beilstein J. Org. Chem. 2014, 10, 2286–2292, doi:10.3762/bjoc.10.238

• pyrazolo[5,1-a]isoquinoline derivative 3a instead of the isoquinoline-based azomethine ylide [28] was obtained in good yield (84%, Table 1, entry 1). Similar yields were obtained when NaHCO3 or K2CO3 were used as base (83% and 86% yield, respectively, Table 1, entries 2 and 3). Several other inorganic or

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• substrates favored the formation of the products. Based on control experiments and aforementioned results, Barbas and co-workers proposed a plausible mechanism and suggested that the high stereoselectivity resulted from steric interactions between the bulky substituent of the phosphonium ylide from the MBH

• proposed that the major enantiomer formed through re-face attack of the ylide onto the Michael acceptor, rather than attack from the sterically hindered si-face. 2.16 Michael additions Asymmetric Michael addition is one of the most studied enantioselective processes in organic synthesis, with many

• ylide intermediate. Subsequent proton transfer and β-elimination of the phosphine catalyst results in a γ-functionalized α,β-unsaturated enoate. The reaction, known as γ-umpolung addition, was reported by Trost [100] and Lu [101] in 1994 and 1995, respectively. Trost employed butynoates, which are

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds

• Miroslav Palík,
• Jozef Kožíšek,
• Peter Koóš and
• Tibor Gracza

Beilstein J. Org. Chem. 2014, 10, 2077–2086, doi:10.3762/bjoc.10.216

• olefination using (methylidene)triphenylphosphorane ylide and final hydrolysis of the acetonide provided the desired C5-substrate 30. The synthesis of substrates 24–28 bearing an allylic hydroxy group is pictured in Scheme 3. At first, the ester group of previously prepared intermediate E-17 was reduced using

Isoxazolium N-ylides and 1-oxa-5-azahexa-1,3,5-trienes on the way from isoxazoles to 2H-1,3-oxazines

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Yelizaveta G. Gorbunova,
• Ekaterina E. Galenko,
• Kirill I. Mikhailov,
• Viktoriia V. Pakalnis and
• Margarita S. Avdontceva

Beilstein J. Org. Chem. 2014, 10, 1896–1905, doi:10.3762/bjoc.10.197

• diazo esters B involved an isoxazolium N-ylide intermediate C formed by an attack of the rhodium carbenoid onto the isoxazole nitrogen. Furthermore, ylide C could undergo either a 1,2-shift to directly generate oxazine E or a ring opening to 1-oxa-5-azahexa-1,3,5-triene D, followed by a 6π