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

Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99

• room temperature for twelve hours. After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography with a mixture of ethyl acetate, petroleum ether and methylene dichloride 1:9:3 (v/v/v) as eluent to give the pure product for analysis. Diethyl

• for 24 hours. After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography with a mixture of ethyl acetate and petroleum ether 1:3 (v/v) as eluent to give the pure product for analysis. Diethyl 3-cyano-1-(1-cyano-2,3-bis(ethoxycarbonyl)-4

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• to the catholyte. The mixture was left under ultrasound irradiation for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 7:3), affording the corresponding pure 1a as an off-white solid. 1

• stopped and cinnamaldehyde (1.0 mmol) was added to the catholyte. The mixture was stirred for 2 h. The solvent was removed under reduced pressure and the residue was extracted with of Et2O (15 mL × 3) and then purified by column chromatography on silica gel (petroleum ether/ethyl acetate 9:1), affording

• chromatography on silica gel (petroleum ether/ethyl acetate 9.5:0.5), affording the corresponding pure esters 3a–c and 4a,b. BMImBF4 Recycling procedure After extraction of product 3a from the solution, the catholyte was placed under vacuum at room temperature for 30 min to remove diethyl ether residues, then it

Electroreductive coupling of 2-acylbenzoates with α,β-unsaturated carbonyl compounds: density functional theory study on product selectivity

• Naoki Kise and
• Toshihiko Sakurai

Beilstein J. Org. Chem. 2022, 18, 956–962, doi:10.3762/bjoc.18.95

• a nitrogen atmosphere (42 min), the catholyte was evaporated in vacuo. The residue was dissolved in diethyl ether (20 mL) and insoluble solid was filtered off. After removal of the solvent in vacuo, the residue was dissolved in 1 M HCl (5 mL)/1,4-dioxane (5 mL) and the solution was stirred at 30 °C

Introducing a new 7-ring fused diindenone-dithieno[3,2-b:2',3'-d]thiophene unit as a promising component for organic semiconductor materials

• Valentin H. K. Fell,
• Joseph Cameron,
• Alexander L. Kanibolotsky,
• Eman J. Hussien and
• Peter J. Skabara

Beilstein J. Org. Chem. 2022, 18, 944–955, doi:10.3762/bjoc.18.94

• ]. This palladium-catalysed cross coupling is preferred over a Stille cross-coupling due to the high toxicity of organotin reagents [37]. Moreover, purification of compound 25 is facile since it can be used for further reactions after re-precipitation in petroleum ether. In a manner similar to [35], it is

• EtH-T-DI-DTT (1) is readily soluble in a dichloromethane/petroleum ether mixture to enable column chromatography. A similar reaction sequence with an analogue of 33 without α-methyl groups at the terminal positions of the molecules was attempted; however, the corresponding ring closure failed. It is

• iodine, anhydrous diethyl ether, 45 °C, 2 h, 3-bromothiophene, [1,3-bis(diphenylphosphino)propane]dichloronickel(II), 45 °C, 14.5 h, 40% [47]; b) n-butyllithium, 2,2,6,6-tetramethylpiperidine, anhydrous tetrahydrofuran, −80 °C, iodomethane, then rt, overnight, 86% [48]; c) n-butyllithium, anhydrous

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• (CC) eluted with a MeOH/H2O gradient solvent system (10% to 100%) to yield six fractions (A–F). The fraction B (570 mg) was then fractionated into subfractions B1–B6 by Sephadex LH-20 CC eluted with CH2Cl2. The subfraction B4 (96.2 mg) was further separated by Sephadex LH-20 CC (petroleum ether (PE

Cathodic generation of reactive (phenylthio)difluoromethyl species and its reactions: mechanistic aspects and synthetic applications

• Sadanobu Iwase,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2022, 18, 872–880, doi:10.3762/bjoc.18.88

• ; (phenylthio)difluoromethyl radical; Introduction Organofluorine compounds containing a difluoromethylene group have been of much interest from biological aspects since the difluoromethylene group is isopolar and isosteric with an ether oxygen [1][2]. Particularly, organic molecules bearing a (arylthio

Thiophene/selenophene-based S-shaped double helicenes: regioselective synthesis and structures

• Mengjie Wang,
• Lanping Dang,
• Wan Xu,
• Zhiying Ma,
• Liuliu Shao,
• Guangxia Wang,
• Chunli Li and
• Hua Wang

Beilstein J. Org. Chem. 2022, 18, 809–817, doi:10.3762/bjoc.18.81

• × 5 mL), washed with H2O (3 × 10 mL), and then dried over MgSO4. After removing the solvent in vacuum, the crude product was purified by PTLC with petrol ether (60–90 °C) and hexane/CH2Cl2 5:1 (v/v) as developer to yield DH-1 (5.9 mg, 62%) as a light-yellow solid; mp > 300 °C; 1H NMR (400 MHz, CDCl3

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• , while other synthetic approaches were explored to obtain these reagents, the SN2 strategy described in this work was the most efficient. Such synthetic alternatives included: first, a sulfur(VI) fluoride exchange (SuFEx) between perfluoroalkylsulfonyl fluorides and the corresponding silyl enol ether

• scalable (i.e., a maximum of 15% by 1H NMR). Finally, due to the concentration of α-iodopropiophenone (6) employed, we detected the formation of a byproduct in the last stages of the optimization, namely the condensation of the desired product with α-propiophenone in the form of an enol ether. Once this

• byproduct was fully characterized by NMR, and the structure was confirmed by SCXRD, we conceived a hydrolysis protocol to break apart the formed enol ether (fully described in section 2.4 of Supporting Information File 1). After brief optimization, we succeeded at recovering the portion of

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• ]. It is prominently used in, e.g., Tom Ford: Tuscan Leather along with notes of leather, muguet, and thyme, defining the character of this scent. The related methyl ether 6 (“raspberry ketone methyl ether”) is also used as odorant but is, in contrast to raspberry ketone (5), “intensely sweet, floral

• of up to 0.35 kg/h for enone 4. In the second step, the obtained 4-aryl-3-buten-2-ones 3 and 4 are selectively hydrogenated in flow using a packed-bed reactor with Raney nickel as catalyst affording raspberry ketone (5) in 91% yield and raspberry ketone methyl ether (6) in 94% yield, respectively

• . For compound 6, both individual steps were combined for a two-step aldol condensation/hydrogenation flow sequence providing raspberry ketone methyl ether (6) on a gram scale in 75% overall yield. Interestingly, also alternative flow protocols for the synthesis of 4-aryl-3-buten-2-ones 3 and 4 were

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• temperature of the nanostructured particles (Figure 4B). The Claisen rearrangement of the electron-deficient aryl allyl ether 9 was chosen to compare the versatility and performance of inductive heating with conventional and microwave heating (Scheme 8A) [50]. The effectiveness of inductive heating is clearly

• reactions (anthracene (33) and maleic anhydride (34) to the cycloaddition adduct 35 and chromene carbaldehyde 36 and enol ether 37 to the diastereomeric pyrano-chromenes 38), Alder-En reactions (oxomalonate diethyl ester (39) and β-pinene (40) to give the α-pinene derivative 41), and the thermal

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• , the residue was subjected to column chromatography with petroleum ether/ethyl acetate 15:1 (v/v) as eluent to give the pure product 3a–m for analysis. rel-(1R,3R)-1'-Benzyl-5'-methyl-6-((Z)-4-methylbenzylidene)-2',5-dioxo-3-(p-tolyl)spiro[cyclohexane-1,3'-indoline]-2,2-dicarbonitrile (3a): white solid

• solution was stirred at 65 °C for six hours. After removing the solvent at reduced pressure, the residue was subjected to column chromatography with petroleum ether/ethyl acetate 15:1 (v/v) as eluent to give the pure product 5a–e for analysis. Ethyl rel-(1S,2S,6R)-1'-benzyl-5'-chloro-3-((Z)-4

• chromatography with petroleum ether/ethyl acetate 15:1 (v/v) as eluent to give the pure products 8a–m for analysis. rel-(3R,3'R)-1,1''-Dibenzyl-5''-chloro-5'-ethoxy-5-methyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (8a): white solid, 71% yield; mp 175–177 °C; 1H NMR (400 MHz, CDCl3

Direct C–H amination reactions of arenes with N-hydroxyphthalimides catalyzed by cuprous bromide

• Dongming Zhang,
• Bin Lv,
• Pan Gao,
• Xiaodong Jia and
• Yu Yuan

Beilstein J. Org. Chem. 2022, 18, 647–652, doi:10.3762/bjoc.18.65

• gel (ethyl acetate/petroleum ether 1:10) to afford the desired products 3a–u. Amination of arenes with phthalimides. Substrate scope of the copper-catalyzed C–H imidation of arenes. Reaction conditions: 1 (2.0 mL as substrate and solvent), 2a (0.10 mmol), CuBr (0.04 mmol) and P(OEt)3 (0.6 mmol) were

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• -aza-18-crown-6 (99) (2.0 equiv) had to be added as a receptor for Cu+. As State-I contains the azacrown ether 99, a potential organocatalyst, and State-II harbors the copper complex [Cu(99)]+ a likely click catalyst, both networked states were expected to be catalytically active, possibly even in an