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

• 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

• NMR using triethyl 1,3,5-benzenetricarboxylate as internal standard. Supporting Information Supporting Information File 92: Experimental procedures and characterization data, original spectra of new compounds, and optimization details. Funding The authors acknowledge the Welch Foundation (A-1907

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

• optimization algorithm allowed them to discover multiple trade-off optima, enabling a scientist to select the ideal catalyst based on the specific requirements of catalytic activity and selectivity, while still accounting for catalyst generality through design of the objectives. Noticeably, data analysis

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

• . Optimization of deuterated Leuckart–Wallach reactiona. Microsomal stability package of deuterated and non-deuterated dihydropyridines. Supporting Information Supporting Information File 86: Experimental and analytical data and copies of NMR spectra. Acknowledgements We thank the UA mass spectrometry and NMR

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

• or its equivalent is indirectly prepared and utilized in only solution phase. Results and Discussion First, we have chosen hex-5-yn-1-ylbenzene (1a) as the model substrate in the reaction optimization (Table 1, method A). The reaction was carried out as follows: Hex-5-yn-1-ylbenzene (1a, 0.5 mmol

• ) was reacted with the Brønsted acid (X equiv) and the fluorine source (Y equiv) in the solvent (4 mL) at temperature of T (°C) for Z hours. The chemical yield of the desired product, (5,5-difluorohexyl)benzene (2a), was evaluated for reaction optimization by using the 19F nuclear magnetic resonance

• 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

Synthesis and reactivity of the di(9-anthryl)methyl radical

• Tomohiko Nishiuchi,
• Kazuma Takahashi,
• Yuta Makihara and
• Takashi Kubo

Beilstein J. Org. Chem. 2024, 20, 2254–2260, doi:10.3762/bjoc.20.193

• two anthryl moieties (Figure 3b, Supporting Information File 1, Figure S1). DFT calculations for structural optimization revealed that the energy difference between two DAntM radical structures with different spin positions, spin localization at the central sp2 carbon and on the anthryl group, is

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

• nucleotides and amino acids, as well as energy molecules, salts, buffer, etc., are added. After successful protein synthesis, further substrates can be added for an enzyme activity assay. Although mimicking of cell-like conditions is an approach for optimization, the physical and chemical properties of CFPS

• various options for soluble substances. Effects of technical additives on the CFPS performance In vitro sfGFP production with additives The in vitro expression of sfGFP, or GFP variants in general, is well established and is often used as a model system for optimization (e.g., with active learning

• deviations in the measurements or by the undefined addition of amino acids via the cell-free extract. Irrespective of this, the high concentration of sfGFP obtained shows the high level of optimization of the synthesis. Therefore, it is not expected that the addition of technical additives will further

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

Electrochemical allylations in a deep eutectic solvent

• Sophia Taylor and
• Scott T. Handy

Beilstein J. Org. Chem. 2024, 20, 2217–2224, doi:10.3762/bjoc.20.189

• electrode materials for electrochemical allylations [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Further optimization employing tin (Table 1, entry 2) enabled near complete conversion to the desired product by using 2.5 F/mol of current passed through the solution at a

Finding the most potent compounds using active learning on molecular pairs

• Zachary Fralish and
• Daniel Reker

Beilstein J. Org. Chem. 2024, 20, 2152–2162, doi:10.3762/bjoc.20.185

• regimes by enabling faster and more accurate identification of more diverse molecular hits against critical drug targets. Keywords: active learning; drug design; machine learning; molecular optimization; potency predictions; Introduction Active learning is a powerful concept in molecular machine

• ][4] and steer molecular optimization for drug discovery [5][6][7][8]. Active learning is particularly powerful during early project stages. However, one major downside is that, at these early project stages, only a very small amount of training data is available to learn from [9] which can be

• , model exploitation can lead to analog identification, which can limit the acquired knowledge and the scaffold diversity of selected hits [1]. We previously showed that leveraging pairwise molecular representations as training data can support molecular optimization by directly training on and predicting

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ). Results and Discussion Reaction optimization Over the past two decades more than 300 various catalytic systems have been proposed for Biginelli chemistry, e.g., simple inorganic and organic acids, metal salts, metal oxides, ionic liquids, phosphines, nanocatalysts, organocatalysts, ion exchange resins [1

• ][4][9] or even visible light-driven methods [25][26][27][28]. We started our study from the optimization of the reaction conditions using β-ketosulfone 1, benzaldehyde and thiourea as model reaction. According to the literature, the reaction has been shown to work best and most efficiently under

• reaction (A) and examples of DHMP (B) and thiopyran-1,1-dioxide (C) containing drugs. Scope of the obtained Biginelli products 2a–q. Synthesis of SO2-containing enastron analogue 2r. Postmodification of the Biginelli product 2a. Optimization of reaction. Supporting Information Supporting Information File

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• Discussion We started our optimization with the reaction between acetonitrile and phenyl trifluoromethyl sulfoxide (1a, Table 1). We firstly chose the same stoichiometry as described in our previous study and tried to reduce the reaction time by the help of microwave heating (Table 1, entry 1). Under these

• . The scope of aryl perfluoromethyl sulfoxides and a selenoxide. The scope of alkyl nitriles. Optimization of the reaction conditions. Supporting Information Supporting Information File 48: Experimental procedures, characterization data of all isolated products as well as copies of NMR spectra for

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• bacterial sugars, the parametrisation of each building block is needed and requires the use of ab initio methodologies, including several steps of charges and electron density calculations, optimization and minimization, making the computational study of bacterial glycans difficult and time-consuming. 2

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

• not have a significant effect on the yield or formation of respective products (Table 1, entry 12). Based on the optimization studies, a combination of KOH in toluene and TBAB (Table 1, entry 2) as phase-transfer catalyst was chosen as the best conditions. Although KOH could saponify the ester group

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• and 3, their conformational ensembles, datasets of a structure and population of each conformer [25], were determined using a Spartan 24 parallel package conformational search tool (Wavefunction Inc, USA), followed by geometry optimization of the most weighted conformers (Boltzmann distribution weight

• [31]. Range-separated hybrid GGA (RSH-GGA) functional, including dispersive interaction with 6-31G* as the polarization basis set (ωB97X-D/6-31G* method), was used for energy and geometry optimization [32]. Bioactivity Cytotoxicity and tyrosinase assays were carried out according to the procedures

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• screening and rapid optimization [46][47]. Homogenous heating and mixing in flow reactors can lead to higher reaction rates and yields. In terms of photochemistry, continuous flow setups provide enhanced light irradiation as well [48][49]. These advantages make flow chemistry a powerful tool for chemical

• methods were tested and after a brief optimization process, zinc dust and HCl in a mixture of EtOH/dioxane proved to be the best conditions in order to maximize the yield and limit the amino ester instability issues (see Table S6 in Supporting Information File 1). By slightly adjusting the reaction time

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

• structures of the intermediate 1CC. Proposed mechanism for the reaction between 1a and PISA in wet HFIP. Optimization of the reaction conditions for the synthesis of 4-substituted isoquinolinone 2aa. Supporting Information Supporting Information File 12: Experimental details, optimization studies, compound

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• importance in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast

• structural hopping strategy, as five- or six-membered heterocyclic aromatic rings are widespread entities in drug discovery [4]. In this sense, any bioactive molecule enclosing a benzene ring in its initial optimization stages could undergo a heteroaromatic replacement. 2-Phenethylamines are notable

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

• acids). In order to expand DELs to the GBB reaction, compartmentation was proposed to confine an acidic catalyst into the lipophilic core of micelles, inaccessible to water soluble DNA. Micelles were made of a sulfonic acid substituted, amphiphilic copolymer 13. After reaction optimization, a narrow

• , respectively. For further investigations, however, CALB was chosen due to its lower cost and easier availability. Optimization of enzyme loading and substrate ratios increased the yield up to 91%. Immobilization of the enzyme on silica particles was not detrimental to the yield, but allowed enzyme recycling

• interactions with the target were synthetized. After optimization of the reaction medium and of the concentration of reactants, and after setting up an analytical method relying on UPLC with tandem quadrupole detector, the on-target KTGS experiments were conducted. In a first set of experiments, a single

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

• . aReaction was done in DMF/AlCl3. bIsolation requires precipitation with 2-propanol. c2 days. Control experiments related to bulky substituted aldehydes. Optimization of the reaction conditions for the synthesis of 2a. Supporting Information Supporting Information File 28: Spectroscopic and analytical data

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• , provided the corresponding iodolactonization product in racemic form with a good yield (80% yield, 50:50 er) [36]. To improve the enantioselectivity in the asymmetric bromolactonization of 2a using NBP and catalyst (S)-1g, the optimization of reaction solvents was also performed. Based on our recent

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

• the four-electron oxidation product 1,1-dimethoxynaphthalen-2(1H)-one (2). Best results were obtained with a carbon/platinum electrode pair, although stainless steel (SS) could also be used as cathode. The experiments were conducted with a 3:1 mixture of methanol/tetrahydrofuran (optimization not

• process, there will always be some extra current passing the cell that does not contribute to the reaction. Our optimization of the current on 1-chrysenol (3b) is given in Table 2. The reaction mixtures were introduced via a 10 mL-injection loop into the stream that was flowing through the Flux cell at a

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

• for methyl malonyl-CoA and malonyl-CoA in the enzymatic conversions. After careful and systematic optimization of the reaction conditions, such as the stoichiometry of the PKS modules and pH, along with the application of a NADPH recycling system, JuvEIV/JuvEV-catalyzed enzymatic conversions of 77–79

• classification, along with parallel discussions of the original biosynthetic pathways, helps organize the current state of the art and offers a comprehensive overview of how synthetic methodologies leverage the natural biosynthetic pathways. The development and optimization of chemo-enzymatic synthetic processes

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• proposed in the initial experiments is not a Lewis acid activator but just a chloride source. Further optimization studies improved the yield to 78% of 4b using a concentration of 0.20 M of the alcohol and 1.4 equiv of 1a (see Supporting Information File 1). Finally, all NHIs were tested under the

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• boronic monoester (18 → 19) followed by ring opening, in accordance to the hemiketal reactions. We decided to directly cleave dioxaborolane 20 after the reaction has stalled to facilitate separation. After a brief optimization of the reaction conditions (details are provided in Supporting Information File

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• given SMILES string undergoes modifications to produce a list of SMILES for each deprotonated C–H bond. We generate min(1 + 3nrot, 20) conformers for each SMILES using RDKit (v.2022.09.4) [16][17], where (nrot) represents the number of rotatable bonds. Each conformer undergoes optimization in dimethyl

• identify the lowest-energy conformer. We then conduct re-optimization in ORCA (v. 5.0.4) [22][23], using the dispersion D4-corrected DFT functional CAM-B3LYP [24][25], the Karlsruhe [26][27] triple-ζ basis set, def2-TZVPPD, and the conductor-like polarizable continuum model (CPCM) [28] as the implicit

• methods are evaluated as single-point calculations or optimization and frequency calculations. For comprehensive details, refer to Supporting Information File 1, section “Benchmark study - computational methods”. Hereafter, we check the geometries for imaginary frequencies and use the total thermal energy