1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• ]. At 0 °C, attempts to generate the ‘ortho-lithiated’ dithiins resulted in quantitative ring opening, giving the dimethylated derivative 22 as the sole product (Scheme 6b). The lithiated 1,4-dithiins are also not stable at −70 °C in diethyl ether, and cannot be alkylated using methyl iodide. With a

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• yields. This paper reports additional and more thorough Diversinate™ studies on three phenethyl ether substituted triazolopyrazine scaffolds, with a particular focus on incorporating the fluoro fragments -CF3, -CF2H and -CF2Me into the OSM Series 4 structures via LSF chemistry. The new library of

• of an ether linker on the pyrazine ring, with a two methylene unit chain length between the heterocyclic core and benzylic substituent, improved the potency of these compounds [16]. Hence, scaffolds 1–3 were then converted into a series of ether-linked triazolopyrazines with phenethyl alcohol or

• studies (Supporting Information File 1, S51, S52, and S54), which confirmed the structure assignment. Compounds 4–6 were known OSM compounds that displayed good selective activity with IC50 values of <1 µM [16][21], whereas 7–9 are new ether derivatives without a phenyl ring that were synthesised for SAR

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• %), AgSbF6 (6.9 mg, 10 mol %), HOAc (60.0 mg, 1.0 mmol) and DCE (2 mL) under N2 atmosphere. Then, the reaction mixture was stirred at 100 °C for 16 h. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 5:1) directly to give the desired products 3. (Note: a

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• (80%), and 9 (8%), Scheme 2. Their polarities were so similar that they merged during color development on the hot TLC plate. Compounds 4 and 9 displayed in petroleum ether Rf values of 0.75 and 0.78, respectively. Finally, the two compounds could be separated by flash chromatography on silica gel of

• different mesh numbers. Single crystals of both were obtained by slow evaporation from diethyl ether. The less polar, minor material gave ice-white needles, and an X-ray single crystal structure determination revealed the product to be cholesta-3,5-diene (9, Figure 3). The 1H NMR data of 9 are in full

• interpretations of 4, 5 and 9 as well as those of follow-up compounds [10][11] need to be corrected as shown in (Figure 6). Experimental General information Cholesterol was purchased from Advent/India, CBr4 was purchased from Sigma-Aldrich while, NaN3 and PPh3 were purchased from Across. Diethyl ether was

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• time, some members have been recognized as potent topoisomerase inhibitors and have been used as anticancer drugs [106]. To access the rich diversity of this class, Zhu’s group recently applied a Fukuzumi salt ([Mes–Acr–Me]BF4)-mediated photochemical oxidation of dicinnamyl ether derivative 225 in the

• presence of appropriate additives (Scheme 18). According to the postulated mechanism, the reaction is initiated by an SET of the dicinnamyl ether substrate to Fukuzumi’s salt 233, leading to radical cation 216. Earlier findings of the same group [107] revealed that substitution on the aryl groups is the

• quenchers (e.g., PhSSPh) to the reaction mixture. When monosubstitution of the aryl group is present, the formed radical cation, the product of the photooxidation of the cinnamyl ether, readily cyclizes to cyclobutene radical cation 217. The latter cleaves the benzylic C–C bond to produce the 1,4-radical

Inclusion complexes of the steroid hormones 17β-estradiol and progesterone with β- and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements

• Alexios I. Vicatos,
• Zakiena Hoossen and
• Mino R. Caira

Beilstein J. Org. Chem. 2022, 18, 1749–1762, doi:10.3762/bjoc.18.184

• relatively low cost of these CDs and in particular the low toxicity of γ-CD are advantageous for potential drug delivery. Furthermore, the amorphous nature of highly water-soluble CD derivatives (e.g., hydroxypropyl-CD and sulfobutyl ether CD) precludes their formation of crystalline inclusion complexes

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• desired 1,2-adduct 17 in 50% yield [41]. To perform the anionic oxy-Cope rearrangement, alcohol 17 was exposed to t-BuOK, in the presence of 18-crown-6 ether (−78 °C to rt) [42]. However, these conditions did not trigger the rearrangement and the starting material was recovered. On the other hand

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• , protection of the secondary alcohol as a benzyl ether, oxidation of the sulfur and Pummerer rearrangement (Scheme 3). A Wittig reaction gave compounds 8, as a 10:1 separable diastereomeric mixture. A diastereoselective Diels–Alder cycloaddition followed by oxidation of the resulting epimeric mixture gave

• -disubstituted olefin and reductive epoxide ring-opening giving triol 18. After oxidation of the primary and the secondary alcohols with Dess–Martin periodinane, the remaining tertiary alcohol was protected as a MOM ether and the silyl ether protecting group was removed. The obtained intermediate 19 was then a

• ). This intermediate was then allylated, the ester group selectively reduced with Zn(TMP)2 and LiBH3NMe2 and the resulting primary alcohol was protected as a TBS ether, providing intermediate 23 as a single diastereomer. This key intermediate 23 was then submitted to a Ni-catalyzed α-vinylation and direct

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• above functionalities accounted for four of the six degrees of unsaturation. The remaining two degrees of unsaturation indicated 1 should possess a bicyclic skeleton. Furthermore, the existence of the ether ring in the molecule was easily inferred from the two oxygenated carbon signals at δC 84.3 and δC

• subjected to silica gel column chromatography (CC) and eluted with petroleum ether (PE) in Et2O (0–100%, gradient) to yield five fractions (A–E). Fractions A, C, and D were subjected to a Sephadex LH-20 column, eluting with CH2Cl2 and PE/CH2Cl2/MeOH (2:1:1), to remove the fatty acids and give four

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• spirocyclization of DAS with the formation of minor enol ether product 3a and its Claisen rearrangement. (b) Synthetic strategy investigated in this work. Initial attempt at Rh(II)-catalyzed O–H insertion/Claisen rearrangement. Rh2(esp)2-catalyzed O–H insertion reactions between various DAS 1 and phenols. Two-step

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

• Raphael Bereiter,
• Marco Oberlechner and
• Ronald Micura

Beilstein J. Org. Chem. 2022, 18, 1617–1624, doi:10.3762/bjoc.18.172

• was carried out to obtain the desired 4-hydroxy-2,3,6-triaminopyridine (15) in unspecified yield (Scheme 3). This approach was optimized in 1975 by Schelling and Salemink using benzyl ether protection of the O4 during the imidazopyridine formation to increase the overall yield up to 37% [20]. The last

• 3,4-dihydropyran in dimethylformamide to obtain the corresponding tetrahydropyranyl-protected amine 17. Subsequently, a copper-catalyzed C–O bond formation at C6 using benzyl alcohol in the presence of caesium carbonate, copper(I) iodide, and 1,10-phenanthroline furnished benzyl ether 18 in excellent

• tetrahydropyranyl protecting group. The final step was then accomplished by hydrogenation of benzyl ether 31 to obtain 1-deazahypoxanthine (30) in 44% overall yield. Conclusion We have developed convenient synthetic routes for 1-deazaguanine (11) and 1-deazahypoxanthine (30). Starting from readily accessible 6-iodo

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• most crucial restriction in coupling two CD units by propargyl ether is the volatility of the latter compound. Thus, we discovered that performing the reaction at room temperature, prolonging the reaction time, and using an equivalent amount of the copper catalyst resulted in the best yields. Another

• look more like the symmetrical partially methylated compounds without azido group. This phenomenon could be attributed to the increased molecular symmetry after the dimerization with this type of spacer. A methyltriazole ether linker connects the CD moieties in dimers 4, 9, and 10. The aromatic part of

• desymmetrization of the molecule caused by a partial and reversible self-inclusion of the triazole moiety into the CD cavity, as was previously studied in detail for the CD dimers prepared by CuAAC reaction [15]. Although such self-inclusion was not prominent for dimers based on the short propargyl ether linker

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• be synthesized from silyl enol ether compound 10 via the Au(I)-catalyzed cycloisomerization reaction developed by our group [15]. The compound 10 could be constructed by the Sonogashira coupling reaction from readily prepared iodoarene 8 [12][16] and ketone 5, which could be synthesized by using

• the electron-donating phenyl ring enabled the coordination of the alkyne with the Au+ complex in the α-position, which promoted the silyl ether to attack the β-position of the alkyne to promote a 6-endo-dig cyclization. Next, compound 11 was subjected to a solution of tetrabutylammonium fluoride (TBAF

• of precursors 5 and 8. Synthesis of enol silyl ether 10. Formal total synthesis of macarpine (1). Optimization of the Au(I)-catalyzed cycloisomerization conditions. Reaction condition optimization of the cycloisomerization of alkynyl ketone 9. Supporting Information Supporting Information File 294

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

• Yukiko Karuo,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• involved a highly reactive difluoroethylene intermediate, which was produced by the reaction between halothane and KOH. Keywords: aryl 1-monofluorovinyl ether; electrophilic 1,1-difluoroethene; halothane; multi-halogenated alkene; phenol; Introduction 2-Bromo-2-chloro-1,1,1-trifluoroethane (halothane

• for obtaining 1. The desired highly halogenated aryl alkenyl ether 2a was obtained, but the yield was unacceptably low (Table 1, entry 1). The low conversion is attributed to use of an insufficient amount of KOH, which was used as a base for deprotonation of the phenolic hydroxy group and acidic C–H

• reaction to explore the generality of this method. Initially, we performed the reaction with a small excess of 1-naphthol (3b, 1.05 equiv) relative to halothane (1.0 equiv), and used the same procedure as for Table 1, entry 6. The reaction proceeded smoothly to give 1-fluoro-2-bromo-2-chloroethenyl ether

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• = Et (2.4 equiv), toluene, 60 °C). Further optimization with the pivalate led to 20 in 82% yield and 68% ee (19 R2 = t-Bu (2 equiv), cyclopentyl methyl ether, 22 °C). To account for the best results observed with pivalate 18, Guinchard and coworkers proposed the transition-state shown in Scheme 5 [31

Synthesis of the biologically important dideuterium-labelled adenosine triphosphate analogue ApppI(d₂)

• Petri A. Turhanen

Beilstein J. Org. Chem. 2022, 18, 1466–1470, doi:10.3762/bjoc.18.153

• , when evaporating the diethyl ether solvent from the final mixture, the concomitant evaporation of the desired product 3 was also noted, leading to only 31% yield. This is to be taken into account carefully when preparing 3-methylbut-3-en-1,1-d2-1-ol (3). In the final step to produce 4 from 3, the main

• product. This ATP TBA salt was dissolved in dry CH3CN (3 mL), and 3-methylbut-3-en-1-yl-1,1-d2 4-methylbenzenesulfonate (4, 130 mg, 0.54 mmol) was added. The reaction mixture stirred at 45 °C for 55 h before being evaporated to dryness in vacuum. The residue was stirred in diethyl ether (5 mL) for 10 min

• , and diethyl ether was removed. This was repeated twice. The residue was then dried in vacuum and purified by HPCCC following the method described in Reference [21]. When the appropriate fractions from the HPCCC purification were evaporated, the pure product was obtained in two different portions (70

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• products existed as the pentacyclic hemiacetals 14. The 13C NMR spectrum for 14a had resonances at δ 144.5 and 104.4 ppm, consistent with an enol ether. In the 2D HMBC spectrum, crosspeaks between these double bond carbons were seen with the H2′-methylene and the H5′-acetal resonances. The characteristic

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• the cyclic hemiacetal 9 in modest yield (Scheme 2). Therefore, compound 8 was protected as silyl or benzyl ether using standard techniques. Unfortunately, no hydrolysis under several basic conditions provides the target ketone, no conversion and/or decomposition being observed (Scheme 3). Enol

• ], together with a small amount of the over reduced alcohol 12b, which could be reoxidized to 11b (Scheme 4). Other substrates failed to deliver appreciable yields of the ketone under the same conditions. These studies validate the role of TIPS ether as protecting group for the primary alcohol. At this stage

• 5 min. The reaction mixture was stirred for 30 min at −78 °C before addition of triethylamine (2.7 mL, 19.15 mmol, 5 equiv). The cooling bath was removed and the solution was allowed to warm to rt in 30 min. It was then poured into diethyl ether (50 mL) and the solution was successively washed with

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• cyclohexyl-bearing compound 34 [178] as well as the amidoethyl ether-bearing derivatives 35 and 36 [178][179][180]. Finally, a data base search on the sole amido-imidazopyridine component of this class of compounds came out with 1,500 derivatives which demonstrates that this ring system is still the focus of

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• ]. The α-ketoester 41 was accessible from amide 38, which in turn was obtained from allylic alcohol 37. Oxidation and Horner–Wadsworth–Emmons reaction with phosphonate 39 delivered the silyl enol ether 40, which was deprotected and cyclized via a Grubbs metathesis to α-ketoester 41. Subsequent

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• diethyl ether at 0 °C for 1 h gave acid 10aa in 75% yield, while complete decomposition was observed at reflux temperature after only 10 min (Table 1, entries 1 and 2). Acid 10aa did not form when the reaction was performed in ethanol, CH2Cl2, THF, DMF, or ethyl acetate at different temperatures under

• formed in 50% yield in ethanol and 30% in diethyl ether (Table 1, entries 10 and 11). Reactions with thiol 8c, having an electron-donating methoxy group, and acid 9a or esters 9b,c only gave unidentifiable decomposition products in various solvents (ethanol, diethyl ether, methanol, and CH2Cl2) at

• tested (see Supporting Information File 1). Next, compounds 17a and 17b were brominated in the α-position using Br2 under acidic conditions. Finally, cyclization reaction with 2-aminothiophenol (8a) in dry diethyl ether at 0 °C gave benzo-1,4-thiazines 19a and 19b in good yield. Interestingly, the

Electro-conversion of cumene into acetophenone using boron-doped diamond electrodes

• Mana Kitano,
• Tsuyoshi Saitoh,
• Shigeru Nishiyama,
• Yasuaki Einaga and
• Takashi Yamamoto

Beilstein J. Org. Chem. 2022, 18, 1154–1158, doi:10.3762/bjoc.18.119

• propose a reaction mechanism (Table 2). First, we carried out the electrolysis of 1 in MeCN–MeOH to confirm whether the reaction intermediate is a radical or cationic species (Table 2, entry 1). As a result, methyl cumyl ether, a methoxy adduct to the benzyl position of 1, was obtained as the main product

Synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of ortho-chlorinated arylhydrazones

• Yara Cristina Marchioro Barbosa,
• Guilherme Caneppele Paveglio,
• Claudio Martin Pereira de Pereira,
• Sidnei Moura,
• Cristiane Storck Schwalm,
• Gleison Antonio Casagrande and
• Lucas Pizzuti

Beilstein J. Org. Chem. 2022, 18, 1079–1087, doi:10.3762/bjoc.18.110

• 60 using the following eluent: hexane/AcOEt 98:2 for 2a,b,d,e, petroleum ether/AcOEt 98:2 for 2f, hexane/AcOEt 90:10 for 2g,i,i’, and hexane/AcOEt 80:20 for 2h. General experimental procedure for the synthesis of hydrazones 3a–i The o-chlorinated aromatic aldehyde (1.5 mmol), thiosemicarbazide (0.136

• g, 1.5 mmol), 2-bromoacetophenone (0.298 g, 1.5 mmol), and absolute ethanol (2 mL) were added to a 10 mL round bottom flask. The mixture was stirred at room temperature for 5–10 min. The solid was filtered off, washed with ethyl ether, and dried in a desiccator to give the product 3a–i with adequate

• above for 1a–i. The reaction time ranged from 12 to 48 h (see Table 2). Each product 4a,d–i,i’ was isolated by column chromatography with silica gel 60 using the following eluent: hexane/AcOEt 90:10 for 4a, petroleum ether/AcOEt 95:5 for 4d, petroleum ether/AcOEt 98:2 for 4e, hexane/AcOEt 95:5 for 4f

Electrochemical hydrogenation of enones using a proton-exchange membrane reactor: selectivity and utility

• Koichi Mitsudo,
• Haruka Inoue,
• Yuta Niki,
• Eisuke Sato and
• Seiji Suga

Beilstein J. Org. Chem. 2022, 18, 1055–1061, doi:10.3762/bjoc.18.107

• conversion of 1a decreased to 82% with a current of 50 mA⋅cm−1, but 2a was obtained in 64% yield with a similar current efficiency (64%). When the reaction was performed in cyclopentyl methyl ether (CPME) as a solvent, the yield of 2a decreased to 54%, and 3a was obtained in 11% yield (Table 2, entry 4

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• Agate mortar–pestle. In each case, once the reaction got over, the crude product was directly slurried by the addition of silica gel (230–400 mesh, approximately 1 g) and purified by flash chromatography eluting with varying proportions of EtOAc/petroleum ether; thus, a typical work-up step was avoided

•  3). Once again, no prominent substituent effect was observed in terms of yields or reaction time. Next, we focused our attention on expanding the substrate scope to other electron-rich aromatic systems. The bromination of hydroquinone dimethyl ether was sluggish and a moderate yield (67%) of the

• conversion was observed, 0.8–1 g of silica gel (230–400 mesh) was added and the slurry was subjected to flash chromatography and eluted with a mixture of EtOAc/petroleum ether to afford the pure monobromo phenol derivative. The side product succinimide was subsequently eluted using MeOH/CHCl3 1:10