Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• ,anti. Then, hydrazones 3 were reacted with zinc and methyl 2-(bromomethyl)acrylate (4). This aza-Barbier reaction was performed in a biphasic medium (THF/aqueous solution of saturated NH4Cl) to avoid the formation of the α-methylene-γ-lactam obtained by intramolecular cyclization of the zinc amide on

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• substrates in the cascade reaction of curcumins employing a biphasic solvent system for the synthesis of highly functionalized cyclohexanones and tetrahydrochromenes. In view of the above, we report herein cascade double and triple Michael reactions of curcumins with arylidenemalonates in the presence of a

• base (KOH) and a phase-transfer catalyst (PTC) in a biphasic medium (toluene–H2O) at room temperature, leading to highly functionalized cyclohexanones and tetrahydrochromenones as major and minor products, respectively, in moderate to high yield and excellent diastereoselectivity. Results and

• , our methodology involves a biphasic reaction medium where the starting material, viz. arylidenemalonate, remains in the organic layer and prevents itself from undergoing saponification because it requires either aqueous or alcoholic (MeOH or EtOH) medium. Furthermore, deprotonation of curcumin

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• -derived hydrazones under harsh reaction conditions. In 2023, the group of Waldvogel presented a formal electrooxidative (3 + 2)-cycloaddition between aldehyde-derived hydrazones 72 and alkenes 73 to yield a large range of N-arylpyrazolines 74 under mild reaction conditions (Scheme 14) [58]. A biphasic

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• -tetrazole component remaining unreacted. To our delight, the use of toluene/water (9:1) as a biphasic solvent system provided quantitative product formation with 90% isolated yield (Table 1, entry 15). Upon trying to reduce the reaction time and performing the reactions at higher temperature, the product

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• hydrochlorination reaction and optimized the stoichiometry and the stirring rate for the hydrochlorination of alkenes with fuming hydrochloric acid (37%) (Table 9) [76]. We found that for biphasic mixtures high stirring rates (1500 rpm) gave significantly improved conversions and that 1 mL of fuming 37

Preparing a liquid crystalline dispersion of carbon nanotubes with high aspect ratio

• Keiko Kojima,
• Nodoka Kosugi,
• Hirokuni Jintoku,
• Kazufumi Kobashi and
• Toshiya Okazaki

Beilstein J. Org. Chem. 2024, 20, 52–58, doi:10.3762/bjoc.20.7

• transition concentrations from isotropic phase to biphasic state, and from biphasic state to nematic phase are lowered, which is consistent with the predictions of the Onsager theory. An aligned DWCNT film was prepared from the DWCNT dispersion by a simple bar-coating method. Regardless of the higher aspect

• ) method [22][23]. The transition concentrations from the isotropic phase to the biphasic state, and from the biphasic state to the nematic phase were inversely proportional to the aspect ratio (L/D) of the SWCNT, following the same trend as the Onsager theory [7][9][11][15][20][23][24]. By using

• dispersions with a higher L/D were successfully prepared utilizing highly crystalline DWCNTs. Indeed, the transition concentrations from the isotropic phase to the biphasic coexisting state and from the biphasic coexisting state to the nematic phase were found to be lower than those in the previous study. In

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• appearance of a solid–liquid biphasic mixture as the components of the DES are water-soluble. A large volume of water should be used since otherwise some DES traces are present in the NMR spectrum of the precipitate. Benzaldehydes having electron-donating or electron-withdrawing groups were studied as well

Enabling artificial photosynthesis systems with molecular recycling: A review of photo- and electrochemical methods for regenerating organic sacrificial electron donors

• Grace A. Lowe

Beilstein J. Org. Chem. 2023, 19, 1198–1215, doi:10.3762/bjoc.19.88

• by Girault, Scanlon and co-workers on photocatalytic water splitting [33][34][35]. They used the redox mediator decamethylferrocene (DcMFc) in biphasic systems and semi-immobilized their photosensitizers and catalysts at interfaces between two immiscible electrolyte solutions (ITIES). This

Honeycomb reactor: a promising device for streamlining aerobic oxidation under continuous-flow conditions

• Masahiro Hosoya,
• Yusuke Saito and
• Yousuke Horiuchi

Beilstein J. Org. Chem. 2023, 19, 752–763, doi:10.3762/bjoc.19.55

• -tube reactors or fixed bed reactors [17][18][19][20]. To maximize this advantage, the gas–liquid biphasic reaction must be controlled under continuous-flow conditions. This reaction requires high mixing efficiency to assure high mass transfer of the gas to the liquid phase and a consequent high

• [23] or a static mixer [24]. Slug-flow is a simple method for passive mixing, but the formation of slug-flow depends on the tube diameter [23], and the reaction rate decreases as the tube diameter increases [25][26]. The gas–liquid biphasic reaction also displays the same characteristic, and a static

• mixer needs to be developed to enable more robust aerobic oxidation under continuous-flow conditions. A static mixer is generally used by inserting it into a tube reactor. In the gas-liquid biphasic flow reaction, the static mixer has to be inserted into the full range of the tube reactor to maintain

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• product in pure form from a crude reaction mixture failed. However, when a mixture of imine 5a and methacryloyl chloride (31) was stirred in a biphasic mixture of CH2Cl2 and aqueous NaHCO3 solution, we were able to isolate and fully characterize aldehyde 32 which would form via the hydrolysis of iminium

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

• addition of ethyl vinyl ketone (EVK), promoted by K2CO3 in a biphasic media (PhMe/H2O), was followed by basic treatment (LiOH) of the keto aldehyde. Since compound 12 bears the desired quaternary carbon of this family of natural products, it was pleasing to reach this milestone, keeping in mind that the

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• prolonged periods of use that would impede the overall product quality. To solve the scalability problem, larger Zaiput membrane separators are available, however, reports of their successful implementation are so far very scarce. These larger systems were however successfully applied in biphasic oxidations

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

• a method for the acetylation of isoamyl alcohol (9) catalyzed by Candida antarctica lipase B (Scheme 3) [26]. A biphasic system consisting of n-heptane and an aqueous buffer solution is used and efficiently mixed in a Corning AFRTM Low Flow reactor providing a fine dispersion of the reaction mixture

• and, thus, a large interface between the phases. Subsequently, the biphasic system is directly separated, employing a PTFE membrane separator, to afford a solution of isoamyl acetate in n-heptane, while the aqueous layer containing the lipase could be recycled. At 60 °C with a residence time of 8.6

• min isoamyl acetate (10) is obtained in 59% yield according to GC analysis [26]. Related methods for the enzyme-catalyzed acetylation of isoamyl alcohol (9) have been developed utilizing biphasic systems, supercritical carbon dioxide as a solvent, or packed-bed reactors with immobilized enzymes [27

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• ) can be readily produced through electrochemical synthesis. This methodology allows the reuse of the electrolyte and demonstrates a significant substrate conversion. Raju and co-workers [94], for instance, reported the electrochemical synthesis of 10 from menadiol (14) using galvanostatic biphasic

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• ], however, many of them involve the use of expensive and complex membrane filters. To reduce cost and increase simplicity we opted to use a ‘home-made’ setup to achieve continuous separation which consisted of a laboratory separating funnel, into which we collect the biphasic reaction output following

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• dioxane gave the crude ammonium salt, which was subjected to biphasic ring closure; the hydrochloride salt was added dropwise to a stirred emulsion of saturated NaHCO3 solution in chloroform [55]. Macrocycle 11 was obtained in acceptable yield as a diastereomeric mixture (dr 87:13), but the diastereomers

High-speed C–H chlorination of ethylene carbonate using a new photoflow setup

• Takayoshi Kasakado,
• Takahide Fukuyama,
• Tomohiro Nakagawa,
• Shinji Taguchi and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2022, 18, 152–158, doi:10.3762/bjoc.18.16

• chloroethylene carbonate, a precursor to vinylene carbonate. A novel photoflow setup designed for a gas–liquid biphasic reaction turned out to be useful for the direct use of chlorine gas. The setup employed sloped channels so as to make the liquid phase thinner, ensuring a high surface-to-volume ratio. When

• ° to achieve a thin substrate layer causing a rapid gas/liquid biphasic reaction. The residence time was estimated to be 15 and 30 seconds, respectively (for the measurement, ethylene carbonate was introduced in the absence of chlorine gas). After the experiments, chlorine gas that remained inside the

• , entry 3). These results suggest that the reaction has to be carried out carefully under dry conditions. Conclusion In this work, we reported that a novel photoflow setup designed for a gas–liquid biphasic reaction turned out to be useful for the C–H chlorination using chlorine gas in flow. Two decades

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• et al. They carried out asymmetric conjugate amination of tert-butylbenzyloxycarbamate (50) to β-nitrostyrene 51 under neutral phase-transfer conditions in the presence of chiral bifunctional tetraalkylammonium bromide (cat. 52) in water-rich biphasic solvent. The reaction proceeded with high ee

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• in dichloromethane, 1.6 mL, 2.57 mmol) was added dropwise. The reaction was continued for three hours, quenched by the addition of ethyl acetate (4 mL) and allowed to come to room temperature. Half-saturated potassium sodium tartrate solution was added (4 mL) and the biphasic mixture was stirred

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• reactive centre dramatically increases the acidity at this position and, in preliminary studies, we found that under biphasic basic conditions 2-oxindole 5 was undergoing alkylation also in the absence of a phase-transfer catalyst (not ideal when designing a catalytic enantioselective process). Despite

• reactions can be occasionally performed even in absence of base under water-enriched/organic biphasic conditions [41][42][43][44][45][46][47]. Taking inspiration from these studies, it was envisaged that by employing base-free neutral reaction conditions – given the likely acidity of substrate 5 – that it

• . Conclusion In conclusion, we have described a base-free protocol for the asymmetric phase-transfer-catalysed SN2 alkylation of densely functionalised 2-oxindole derivatives, employing a biphasic water-rich solvent system. To the best of our knowledge, these base-free neutral reaction conditions have never

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• flow reacting acetone with a wide range of aldehydes. In batch, acetone-based aldol reactions are typically performed under biphasic conditions by slow addition of the aldehyde to an acetone/NaOH mixture kept at low temperatures. Upon scale-up, this carries with it problems such as inefficient mixing

• mixture is biphasic, and a preliminary separation is carried out before entering the reactor coil. After discontinuous purification procedures, the product 82 was yielded in 98% purity (72% yield). The second step, instead, is an acid-catalysed cyclisation which employs the same tubular reactor at lower

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• -substituted boronic acids [14][15]. An optimisation study showed that the presence of AgTFA (dehalogenation reagent) and NH4PF6 (Pd(II) stabilizing salt) in the reaction mixture was necessary. Additionally, the solvent was changed from a methanol/water mixture to a DCE/water biphasic system. It was also

Nitroalkene reduction in deep eutectic solvents promoted by BH₃NH₃

• Chiara Faverio,
• Monica Fiorenza Boselli,
• Patricia Camarero Gonzalez,
• Alessandra Puglisi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2021, 17, 1041–1047, doi:10.3762/bjoc.17.83

• was washed with water (2 × 4 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica as stationary phase; eluent: n-hexane/ethyl acetate). Recycling experiments with liquid–liquid biphasic separation In a

Mesoionic tetrazolium-5-aminides: Synthesis, molecular and crystal structures, UV–vis spectra, and DFT calculations

• Vladislav A. Budevich,
• Sergei V. Voitekhovich,
• Alexander V. Zuraev,
• Vadim E. Matulis,
• Vitaly E. Matulis,
• Alexander S. Lyakhov,
• Ludmila S. Ivashkevich and
• Oleg A. Ivashkevich

Beilstein J. Org. Chem. 2021, 17, 385–395, doi:10.3762/bjoc.17.34

• quaternization proceeded regioselectively using the t-BuOH/HClO4 system [25]. Further, the salts 7 were treated with sodium hydroxide in the biphasic system water/chloroform giving aminides 8, which were extracted from the reaction mixtures by chloroform. The obtained aminides 8 are yellow solids and soluble in