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

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• protocol for the electrophilic bromination of arenes, mainly phenols [28][29]. Accordingly, the bromination reaction was initially explored by mixing PIFA and AlBr3, which gave an acceptable yield (84%). However, other iodine(III) reagents were tested as oxidants during the optimization process. Thus, when

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• were degenerate (i.e., 10/11 and 14/15), reducing the number of distinct structures to 22. However, due to the considerable flexibility of the five-membered ring and the low barrier for pyramidal interconversion of the N–H moiety, some inputs converged to the same isomer post-geometry optimization

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• the optimization studies mentioned above, the catalytic system I (15 mol %)/A5 (30 mol %) in CHCl3 (1 mL) at room temperature (30–32 °C) was selected as the optimum reaction conditions (Table 1, entry 12). Under identical optimized reaction conditions, the catalytic system II (15 mol %)/A5 (30 mol

• measured by HPLC analysis using a stationary phase chiral column. Synthesis of 3aa on preparative scale. Proposed reaction mechanism. Optimization of reaction conditions.a Supporting Information Supporting Information File 2: Additional optimization studies, characterization data of compounds 3aa–na and

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• mechanistic scenario. Application scope. Proof-of-concept for the analogous oxidative α-nitration. Optimization of the α-azidation of β-ketoester 1aa. Control experiments using different hypervalent iodine speciesa. Supporting Information Supporting Information File 24: Full experimental and analytical

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• be less-suited for our azlactone protocol, as exemplified for derivative C1 (Table 1, entry 9). Accordingly, we carried out our final optimization using Maruoka’s catalyst B2 (Table 1, entries 10–14). By testing different bases and lower temperatures as well as lower catalyst loadings we identified

• ammonium salt-catalyzed β-selective addition of compounds 2 to allenoates 3 (B), and the herein investigated β-selective addition of azlactones 1 to allenoates 3 (C). Application scope (conditions as detailed in Table 1, entry 13). Azlactone opening reactions. Optimization of the addition of azlactone 1a

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• plate as the cathode, was electrolyzed with a cell potential of 2.3 V (corresponding to an initial anodic potential of 0.10 V versus the ferrocenium ion/ferrocene redox couple) under the irradiation of 400 nm light-emitting diodes (LEDs). Through systematic optimization, we found that the use of readily

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• delivered synchronously. Substrate scope of primary amines 3. Conditions: reactions conducted with 2 (0.2 mmol) and 3b–y (2.0 mmol) were stirred in DME (2 mL) at 60 °C; isolated yields. Gram-scale reaction and successive one-pot synthesis. Synthetic manipulation. Optimization studies.a Supporting