Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• consistent with H-bonding between HFIP and 2c, which results in a more potent oxidant and gives rise to the observed HFIP-promoted olefin aziridination chemistry. A number of observations are relevant to the mechanism by which unactivated olefin aziridination is accomplished by the HFIP-activated

• be unreactive towards sulfonamide (Scheme 4e), suggesting that epoxidation is not on path to the observed aziridines. For discussion of side-products and reaction mass balance, see Figure S4 (Supporting Information File 1). Based on these observations, we favor a mechanism in which H-bond activated

• give rise to epoxidation products. Epoxides are not on-path to the observed aziridines. f) Proposed reaction mechanism. Optimization of HFIP-promoted aziridination of cyclohexene (1a). Conditions: 0.20 mmol 1a, 0.40 mmol PhINTs 2a, 1.0 mL HFIP, N2 atmosphere, 20 °C, 16 h. Yield was determined via 1H

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• include the development of ACE (Asymmetric Catalyst Evaluation) [19][20], AARON (Automated Reaction Optimiser for New Catalysts) [21] or CatVS (Catalyst Virtual Screening) [22]. Such tools have been extensively reviewed in the past years [23][24][25]. Based on a known mechanism, the tools calculate the

• physicochemical descriptors. A prominent early example are Hammett parameters, developed in 1937 [26][27], that relate substituent parameters to the equilibrium constant of the deprotonation of a substituted benzoic acid. The derived substituent parameters are used to gain insight into the mechanism of reactions

• also the structure for which the descriptors are considered. This can either be ensured by expert-knowledge of preselecting relevant structures, for example based on a known mechanism, or by considering information from the entire conformer ensemble. Parallel to the evolution in modelling steric

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• increased the overall yield of the reaction (Table 1, entry 5). In summary, minimal formamide (1–2 equiv), excess [D2]-formic acid, and heating to 170 °C in a microwave reactor for 5 minutes is expected to give excellent yields in good deuteration %. A tentative mechanism to [D3]-formamides is shown in

• utility for the drug-hunting community at large. Competitive examples of D2-benzylamine formation via phenyl-nitriles. Proposed tentative mechanism of [D3]-formamide formation via modified Leuckart–Wallach reaction with [D2]-formic acid. Ugi-4CR products: no deuterium scrambling observed. Ugi-3CR products

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• electricity was passed to the solution. A plausible reaction mechanism for the current reactions is described in Scheme 3. The reaction of carbon–carbon triple bonds and H+ species, which are derived from the Brønsted acid (in method A) or EGA (in method B), gives the vinylic carbocation intermediate A, which

• for 2a. Plausible reaction mechanism. Optimization of the gem-difluorination of hex-5-yn-1-ylbenzene (1a) to form difluorinated compound 2a (method A). Scope and limitations. Supporting Information Supporting Information File 84: Experimental procedure, characterization data of compounds and copies

Cell-free protein synthesis with technical additives – expanding the parameter space of in vitro gene expression

• Tabea Bartsch,
• Stephan Lütz and
• Katrin Rosenthal

Beilstein J. Org. Chem. 2024, 20, 2242–2253, doi:10.3762/bjoc.20.192

• a known mechanism that positively influences CFPS reactions [25]. Interestingly, increasing the concentration of PEG-8000, and thus increasing the viscosity and macromolecular concentration of the CFPS solution towards the properties of the cytoplasm, has a negative effect on the sfGFP synthesis

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• substituents has a lower Ea than DBA with electron-donating substituents. DFT calculations The reaction mechanism was investigated by computational calculations. The reaction mechanism between 5 and benzyl azide was supported by the ωB97X-D/6-31G(d,p) calculations with the CH2Cl2 polarizable continuum model

• . (a) Strain-promoted azide–alkyne cycloaddition between DBA 5 and benzyl azide and (b) 1H NMR spectral change at 30 °C in CDCl3. Arrhenius plots of the rate constants for the reaction between 5 and benzyl azide in CDCl3. Proposed reaction mechanism for the formation of compound 6a. Free energy

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• yield is stated. Keto/enol ratio of 3 was determined by 1H NMR spectroscopy. Gram-scale hydrolysis reactions of 1a. Proposed mechanism for formation of β-keto thioesters 2 and β-keto amides 3. Optimization of the reaction conditions. EcoScale calculations and results for the synthesis of 2a and 3a [75

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• -substituted 1,3-diketone 1e. Conditions B: 1e (0.3 mmol), 2a (0.45 mmol), AcOH (30 mol %), molecular sieves 3 Å (300 mg) and acetone (1 mL), 60 °C. Proposed mechanism for the formation of meta-substituted anilines 3 via three-component benzannulation. Supporting Information CCDC 2356152 (1g), 2356151 (3ab

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• '-azobis(isobutyronitrile) (AIBN). Then, E• adds to isocyanide 1 to form imidoyl radical 2, which abstracts hydrogen from E–H. The addition reaction proceeds by a radical chain mechanism, producing the 1,1-addition product 3 with regeneration of E•. In method 2, E• is generated by homolysis of a heteroatom

• mechanism. In the case of tertiary alkanethiols and arylmethanethiols, the corresponding imidoyl radicals 2 decompose to give tertiary alkyl and benzylic radicals, respectively, to form isothiocyanates 5. On the other hand, we have investigated the radical addition of diphenyl disulfide to isocyanides under

• mechanism. Radical addition of group 14 compounds to isocyanides Group 14 compounds with an E–H or E–E bond (E = Si, Ge, Sn) have no lone-pair electrons and therefore cannot generate group 14 heteroatom radicals by homolysis via the n–σ* transition. To generate group 14 heteroatom radicals, the hydrogen

Cage-like microstructures via sequential Ugi reactions in aqueous emulsions

• Rita S. Alqubelat,
• Yaroslava A. Menzorova and
• Maxim A. Mironov

Beilstein J. Org. Chem. 2024, 20, 2078–2083, doi:10.3762/bjoc.20.179

• in favor of the second mechanism. To identify the structure obtained on the surface of the droplets during the formation of the Pickering emulsion, we used fluorescent labels. Aminofluorescein was introduced into the CMC composition with a ratio of 3 mg per 1 g of cellulose using condensation in the

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

• double Michael adduct 3n in 56% yield (Table 2, entry 14). A plausible mechanism for the cascade double and triple Michael reactions is shown in Scheme 2. At first, the enolate I of curcumin 1 adds to arylidenemalonate 2 in a Michael fashion resulting enolate II. The ester enolate II might remain in

• reported in due course. Biologically active derivatives of cyclohexanones. X-ray structure of 4a (CCDC 2351387). Origin of stereoselectivity in the double Michael addition. The Michael donor–acceptor reactivity of curcumin: previous vs present work. A plausible reaction mechanism. Scale-up reaction

Understanding X-ray-induced isomerisation in photoswitchable surfactant assemblies

• Beatrice E. Jones,
• Camille Blayo,
• Jake L. Greenfield,
• Matthew J. Fuchter,
• Nathan Cowieson and
• Rachel C. Evans

Beilstein J. Org. Chem. 2024, 20, 2005–2015, doi:10.3762/bjoc.20.176

• species produced on water radiolysis may therefore play a complicated role in inducing Z–E isomerisation via a number of different mechanisms. No matter the mechanism, the morphology changes on X-ray irradiation appear consistent with the hypothesis that the E isomer is reformed, as shown by the return of

• E isomer after X-ray irradiation (Figure S7, Supporting Information File 1). To further investigate the mechanism for Z–E isomerisation using X-rays and associated structural changes, we conducted an identical experiment using D2O instead of H2O. The change of solvent leads to an increase in the

• micelles, from 20 to 25 Å after 50 s of irradiation (Figure 3d), but the morphology transition to the ellipsoidal shape is not complete. This could be due to both the slower rate of D+ exchange with the photoisomers, leading to a slower rate of Z–E isomerisation via this mechanism. Furthermore, the

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

• access to diazo compounds as either synthetic intermediates or products. A special attention is paid to the reaction mechanism with the aim to encourage further development in this field. Keywords: C–H functionalization; diazo compound; electrosynthesis; hydrazone; nitrogen-containing heterocycle

• regardless of the electronic properties of the substituents on the N-phenyl ring. When dissymmetric diaryl ketone-derived substrates were employed, the C–N bond formation occurred selectively on the most electron rich aromatic ring. According to the proposed mechanism, this dehydrogenative cyclization of

• hydrazones initiated with the SET anodic oxidation of the hydrazone and deprotonation to form the N-centered radical 10. After aza-cyclization on the aromatic ring, a second SET oxidation and deprotonation delivered the heterocycle 9. This mechanism was supported by cyclic voltammetry analysis of a model

Radical reactivity of antiaromatic Ni(II) norcorroles with azo radical initiators

• Siham Asyiqin Shafie,
• Ryo Nozawa,
• Hideaki Takano and
• Hiroshi Shinokubo

Beilstein J. Org. Chem. 2024, 20, 1967–1972, doi:10.3762/bjoc.20.172

• CH2Cl2. Cyclic voltammogram of 2a in CH2Cl2. Supporting electrolyte: 0.1 M Bu4NPF6; working electrode: glassy carbon; counter electrode: Pt; reference electrode: Ag/AgNO3; scan rate: 50 mV⋅s−1. Reaction of norcorrole 1 with AIBN. Reaction of norcorrole 1 with V-40. Plausible reaction mechanism

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• -carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N1- and N2-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N1-substituted products when cesium is present and

• compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways. Keywords: DFT; indazole; indazole substitution; mechanism; N1-substituted indazole; N2-substituted indazole; regioselectivity; Introduction Indazoles constitute an important class of

• the chelation pathway proposed in Figure 5, we hypothesized that 18 (Figure 9) would provide a model for exploring the mechanism further. If chelation between an electron-rich oxygen atom from a substituent and a Lewis acid (such as Cs+ or P+) were taking place, we would expect regioselectivity for

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• - or 4-substituted isoquinolinone derivatives with excellent chemoselectivity. These interesting findings led us to investigate the reaction mechanism. To gain insight into the mechanism and chemoselectivity of the reactions above, we performed a control experiment. With acetonitrile as the solvent, a

• aforementioned control experiment and literature precedents, we proposed a mechanism for the formation of 4-substituted isoquinolinone derivatives, including 2a. The reaction begins by tautomerization of 1a, and PISA undergoes an electrophilic reaction with 1a' to form the iodane intermediate A. The iodane A

• HFIP (3.0 mL) at room temperature. Isolated yield is stated. aThe yield of 2k was 56%. bThe yield of 2m was 24%. cThe yield of 2n was 11%. Control experiment to test for radical intermediates. Proposed mechanism for the reaction between 1a and PISA in anhydrous acetonitrile. Two other resonance

Electrochemical radical cation aza-Wacker cyclizations

• Sota Adachi and
• Yohei Okada

Beilstein J. Org. Chem. 2024, 20, 1900–1905, doi:10.3762/bjoc.20.165

• piperidine 17 were obtained in good mass balance under non-electrochemical conditions. Although the detailed mechanism remains an open question, the electrochemical aza-Wacker cyclizations might be radical reactions rather than ionic ones, since the six-membered piperidine was not obtained from the

• . Synthetic outcomes and cyclic voltammetric studies suggest that the reactions are initiated by single-electron oxidation of the alkenes instead of the aryl sulfonamides. Although the detailed mechanism remains an open question, the electrochemical radical cation aza-Wacker cyclizations might be radical

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• -free conditions at room temperature for 2 h [16]. Although thiamine had already been reported to be effective in other chemical transformations and its role in carbonyl activation in vivo through its thiazole ring is well known, no mechanism of action in the GBB condensation was proposed by the authors

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• mechanism, see Supporting Information File 1). Such results with previous reports on DMSO acting as a methine source in the synthesis of heterocyclic compounds [35][36] are opening a new avenue for the green synthesis of non-substituted 5-deazaalloxazines in a pseudo MCR fashion. Conclusion In summary, we

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• domain. The findings of this study provide valuable insights into the effects of lanthipeptides on S. epidermidis, and confirm the previous results acquired during the antimicrobial activity assays. Further studies are needed to confirm the mechanism of action of these lanthipeptides and their molecular

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• benzodiazepinones, where the protonation would be exclusively controlled by the chiral amine in the synthesis of 6. Moreover, this proposed mechanism also explains the spontaneous cyclization in the absence of a base when 3-bromopropanamine was used (Scheme 8). Moreover, we envisaged the possibility of obtaining

• -phenylglicine. Synthesis of pyrrolopiperazinone 11 using (S)-α-methylbenzylamine. Proposed mechanism in the spontaneous cyclization of Ugi adducts obtained from arylglyoxals and deactivated amines. Synthesis of pyrrolopiperazinoquinazolines 13. Synthesis of piperazinoquinazoline 14. Synthesis of

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• ]. Studies by Swenton’s [41][53] and Barba’s [54] groups have established that a phenoxonium ion is formed, which is supported by further studies [37][39]. Based on this prior knowledge and our results, a mechanism for the anodic oxidation is proposed in Scheme 3. After two single-electron transfers [38], a

• the hydroxy group is available for oxidation, while o-quinones are formed when the para-position is part of the conserved polyaromatic skeleton. All results are in accordance with an oxidation mechanism going through a phenoxonium cation. Experimental The substrates 1a,b and 6a,b were obtained from

• performed under neutral or weakly basic conditions. Anodic oxidation reported by Swenton et al. [37]. Proposed mechanism for the formation of p-dimethoxy acetals in the anodic oxidation of 1b and 3b. Electrode and electrolyte effects on the electrochemical oxidation of 2-naphthol (1a).a Anodic methoxylation

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• yields (82–85%) (Scheme 28). The authors proposed a free radical mechanism facilitated by hydrogen peroxide, generating a primary radical at the terminal nitrogen atom -CO-HN• which then adds to the carbon atom of the imino group. The reaction mechanism was substantiated by theoretical calculations

• . According to the mechanism, the heterocyclic ring closes by the attack of the bulky radical -CO-HN• over the α steroidal side to circumvent the 1,3-diaxial interaction with the methyl group at C-10. Spiro-1,3,4-oxadiazoline steroid Shamsuzzaman et al. achieved the synthesis of 5’-acetamido-3’-acetyl-(3R

• –water–NaOAc mixture. Spiro heterocycle 99 was obtained in 52% overall yield as a single product (Scheme 29). The reaction mechanism was elucidated based on the hard and soft acid and base theory. Spiro-1,3,4-thiadiazoline steroids In 2006, Mazoir et al. [56] reported the synthesis of 4α,14α-dimethyl-5α

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• I (9). As a pioneering investigation to elucidate the mechanism of this essentially identical allylic oxidations by Fe(II)/2OG-dependent dioxygenase, Dairi and co-workers conducted in vitro enzymatic conversions with the homologous enzyme Bsc9, derived from Alternaria brassicicola ATCC96836 [24

• processes. The mechanism was initially postulated by Dreiding [30], and supported through isotope-labelling studies conducted by Abe and co-workers [31][32][33]. Subsequently, Cox et al. have elucidated the key enzyme SorbC responsible for the dearomatization process [34][35]. Scheme 4A illustrates the

• families, known as bistetrahydroisoquinoline (THIQ) alkaloids, share a highly functionalized pentacyclic scaffold with different aromatic ring oxidation states and sidechain structures [90][91][92][93]. The biosynthetic mechanism of 5 has been extensively studied by gene disruption and reconstruction of in

A fiber-optic spectroscopic setup for isomerization quantum yield determination

• Anouk Volker,
• Jorn D. Steen and
• Stefano Crespi

Beilstein J. Org. Chem. 2024, 20, 1684–1692, doi:10.3762/bjoc.20.150

• ]. Among the different switches known in the literature, azobenzene is a textbook example of a photoswitch operating via a double bond isomerization mechanism, with the first reports of its trans-to-cis interconversion under direct sunlight dating back to the work of Hartley in 1937 [2]. Over the decades