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

• solution of Bu4NBF4/CH2Cl2 containing substrates might also promote the same reactions (Figure 1, reaction 6, electrochemical method). Currently, electrochemistry can be regarded as a promising technique in organic synthesis, because heavy-metal reagents can be avoided for the oxidation or reduction of

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 strong negative effect on the in vitro synthesis of sfGFP. Although the concentration of inorganic ions and osmolarity are close to physiological conditions at a concentration of 2% choline chloride, a reduction of sfGFP production to only 2% was measured for choline chloride/urea and 41% for

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

• there are many reasons for this renewed interest, two major motivations are the unmatched control of oxidation or reduction potential that can be achieved and the environmentally friendly aspect of having electrons as the only consumed reagent. This latter reason is certainly an advantage in many cases

• product, although in this case, reduction of the nitro group to an amino group was observed and the resulting 4-aminobenzaldehyde is likely too electron-rich to undergo allylation. The use of other halides was also explored (Table 3). Switching to allyl chloride (Table 3, entry 2) did result in partial

• reducing the waste generated in these allylations. While non-sacrificial graphite electrodes had failed to result in any reaction, it seemed possible that the use of a catalytic amount of tin metal or a tin salt with graphite electrodes would result in a superior reaction due to in situ reduction and/or

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

• Graphis scripta var. pulverulenta, G. prunicola, and G. cognata [43][45][46][165]. Their structures were proposed based on NMR-spectroscopic investigations and were unambiguously confirmed by total syntheses [44][166]. Graphislactone A had already been obtained previously from the synthetic reduction of

• ring was isolated from Ulocladium botrytis [219] and Microsphaeropsis olivacea [167]. Its structure was unambiguously confirmed by NMR spectroscopy and by total syntheses [44][220]. Ulocladol is a tyrosine kinase (p56lck) inhibitor leading to a reduction of enzyme activity to 7% at 0.02 µg/µL) [219

• ] and from Talaromyces sp. [243]. It showed significant α-glucosidase inhibition with an IC50 value of 2.2 μM [244] and was a potent scavenger of DPPH and of nitrite [243]. Decarboxyaltenusin (50) was reported in 1974 to be obtained by chemical decarboxylation of altenusin (47) and by reduction of

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

• radicals abstract hydrogen from the tin hydride or hydrosilane, and the reduction reaction proceeds with the concomitant formation of stannyl or silyl cyanide 15 as byproducts (Scheme 9a) [38][43]. In the presence of acrylonitrile, the formed alkyl radical can add to acrylonitrile, affording the addition

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

• yield of 15%. The main product obtained was phenyl(trifluoromethyl)selane, a reduction product of the selenoxide. Despite a low yield, this result is encouraging because it is the first example of rearrangement with aryl trifluoromethyl selenoxide. We further investigated the generality of the reaction

• chain, and the alkyl chain linking the cyano functional groups. The [3,3]-sigmatropic rearrangement of perfluoroalkyl selenoxides needs to be optimized to improve the yield and decrease the amount of reduction product. The complete evaluation of the potential of these new compounds will be provided in

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

• , Supporting Information File 1). Fits to the data show a return to the cylindrical micelle morphology present in the E isomer, but with smaller dimensions of 98 Å length (cf. 136 Å in the E isomer), and radii of 13 and 15 Å in the polar and equatorial directions (Table 1). A similar reduction in micelle size

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

• have been harnessed as valuable intermediates in Wolff–Kishner reduction reactions [12][13][14] or for the synthesis of various olefins via diazo or vinyllithium intermediates in the Bamford–Stevens reaction [15] and Shapiro reaction [16], respectively [17]. SAMP/RAMP ((S)/(R)-1-amino-2

• hydrazone and (ii) the ammonium cation would provide a performant proton source to counterbalance the overall process, thereby protecting the diazo product from cathodic reduction (akin to the conversion of 132 into 135 in Scheme 27). Based on these studies, the authors proposed the initial anodic formation

• + (E1/2(TAC2+/TAC+) = +1.3 V vs SCE). Subsequent SET between highly oxidizing photoexcited species TAC2+* (E1/2(TAC2+*/TAC+) = +3.3 V vs SCE) and 150 generated distonic species 151 by denitrogenation. After Wagner–Merweein shift, the resulting radical cation 152 would undergo SET reduction from an

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

• the electrophile [16][17][18]. In addition, C–C double bonds of the norcorrole skeleton outside the π-delocalization pathway exhibit a reactivity similar to an alkene to afford hydrogenated norcorroles by hydrogenation [19] or reduction with hydrazine [20] and [3 + 2]-cycloadducts with 1,3-dipoles [21

• CH2Cl2 were examined using cyclic voltammetry (Figure 4). Macrocycle 2a exhibited one reversible oxidation wave at 0.44 V and two reversible reduction waves at −0.85 V and −1.14 V. The electrochemical HOMO–LUMO gap of 2a is 1.29 V, which is larger than that of 1a (1.08 V) [2]. DFT calculations We next

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• -difluoroethylene was based on 1,2-dichloro-1,2-difluoroethane (HCFC-132) [48][49][50][51][52], prepared from 1,1,2,2-tetrachloro-1,2-difluoroethane (CFC-112) by reduction using lithium aluminum hydride [48][49][50][51] or photoreduction (Scheme 2) [51]. The resulting HCFC-132 reacted with zinc [47][49][52] or

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

• heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation–hydrolysis–reverse amidation protocol. Keywords: amino acids; DEL

• that α-heteroaryl acetates accessed through Negishi coupling can be used as key intermediates towards NCAs (Scheme 1c). Indeed, oximation of these motifs followed by reduction gave access to the desired NCAs. Results and Discussion Negishi cross-coupling step The Negishi reaction provides convenient

• amino group by reduction. We reasoned that increasing the sp2 fraction and the rigidity of the whole structure will lead to increased stability of these derivatives. The first exploratory attempts demonstrated the easy preparation and the high bench stability of the oxime derivatives, therefore we opted

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• −1.2V to −1.3 V region (Table 1). In case of S2, the second reduction peak corresponds to the reduction of the carbonyl group. Thus, the electrochemical window for the new salts exceeds 3.5 V; that makes their molten forms perspective for application as ionic liquids. As follows from Table 1, oxidation

• of the starting amines A1–A3 occurs at ca. 1–1.1 V vs Ag/AgCl, KCl(sat.). The electrochemical study of PIFA reduction showed a broad irreversible peak with the onset potential value of +0.93 V (vs Ag/AgCl, KCl(sat.)). Thus, it is sufficiently strong to perform oxidation of diarylamines A1–A3, as it

• direction of the potential sweep is changed after passing the first reduction peak of salt S2, the new peak appears at the potential of 0.89 V that completely coincides with the first oxidation peak of the amine precursor. The CV curve for the diarylamine, in its turn, exhibited (in the reverse scan after

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

• step to driving bond formation and/or cleavage. Therefore, the discovery of new modes for activation leads to reaction advancements. Electrochemical [1][2][3][4][5] and photochemical [6][7][8][9][10] reactions that induce single-electron reduction and oxidation are widely used in modern synthetic

• organic chemistry [11][12][13][14][15]. Single-electron oxidation of bench-stable substrates can generate radical cations that offer unique reactivities as intermediates for various bond-formation processes (also true for reduction). Because the reactivities of radicals and ions are fundamentally

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

• ). Later, the authors expanded the histaprodifen family by SAR exploration of small substituents in the phenyl rings (compounds 67–78, Scheme 11) [59][60]. While pEC50 values varied very subtle, a histamine relative potency screening revealed a general reduction in potency. Following the same assay

• -ring bioisostere, but as carboxylic acid one, Schwarz et al. [79] developed tetrazole-based pregabalin bioisosteres 113–118 (Scheme 18). The target protein α2-δ is involved in neurotransmitters release reduction, as a model of anxiety and neuropathic pain. In general, submicromolar affinities were

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

• incorporated into the second isocyanides. The utility of this protocol was evaluated by conducting a gram-scale synthesis using 10 mmol of all precursors and there was no significant reduction in the yield of products. Al-Tel et al. [62] developed a synthetic strategy where a Michael acceptor (a conjugated

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

• , value for Ar = Ph] [14][15][16][17][18] (Figure 1B). 5-Aryldeazaalloxazines 2 have been found to be even more powerful reductants than 1 due to their more negative ground-state reduction potential by ca. 300 mV. Moreover, 2 exhibits higher photostability than 1. Consequently, 5-aryldeazaalloxazine 2f

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• major products were phenyliodane 23, presumably a result of ligand exchange and reduction, and iodoalcohol 18. Different solvents, temperatures and activators were investigated and the results are shown in Table S3 in Supporting Information File 1. Fluorobenzene was only ever observed in trace amounts

Synthesis and characterization of 1,2,3,4-naphthalene and anthracene diimides

• Adam D. Bass,
• Daniela Castellanos,
• Xavier A. Calicdan and
• Dennis D. Cao

Beilstein J. Org. Chem. 2024, 20, 1767–1772, doi:10.3762/bjoc.20.155

• undergo reversible chemical reduction processes, as determined by cyclic voltammetry in CH2Cl2 solvent (Figure 4). There are two factors at play. The imide substitution is impactful as the N-phenyl derivatives are roughly by 100 mV easier to reduce than the N-hexyl analogs. The anthracene scaffold also

• lends itself to a more facile reduction process, with an approximately 150 mV shift of the event toward more positive potentials for 8-R vs 7-R. When compared to other structural isomers, aromatic diimides with 5-membered cyclic imides tend to be slightly harder to reduce than those with 6-membered

• title compounds indicates that they are optically and electronically similar to previously reported naphthalene and anthracene diimides, absorbing/emitting light in the visible region and readily undergoing one-electron-reduction processes. As such, this work opens the possibility of incorporating the

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

• with a reduced reactivity in the synthesis of 3H-benzo[e][1,4]diazepin-5-ones, heterocycles previously synthesized by our research group through Ugi/Staudinger/aza-Wittig and Ugi/reduction/cyclization sequences, using 2-azidobenzoic [20] and 2-nitrobenzoic [21] acids, respectively. The first

• chromatography column, while the more eco-friendly second strategy needs an additional stage for the reduction of the nitro group on the Ugi adduct. In order to find a more efficient synthesis, we thought that the second nitrogen in the diazepine nucleus could be incorporated without the need of surrogates or

• reaction took place with a α,3-like relative configuration on the major diastereomer, similar to that obtained for the Ugi/Staudinger/aza-Wittig sequence and complementary to that observed for the Ugi/reduction/cyclization sequence (see Supporting Information File 1, Figure S2). With the aim of building

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

• showed irreversible oxidation processes within the oxidative potential window, scaling from 0.79 V to 1.10 V vs Fe/Fe+. The oxidation peak potential difference between isomers of chrysenols 3 and phenanthrols 6 was 20–310 mV. No reduction peaks were observed in the reverse scan in solutions of neither

• chrysenols nor phenanthrols, suggesting a chemically irreversible reaction of the radical cation intermediate with the ensuing product no longer being electrochemically active within the potential window of the CV scans. However, a reduction peak was observed for compound 1b (see Figure S2 in Supporting

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

• protecting group yielded the corresponding hydroxyalkynyl derivative 4. Subsequent Lindlar reduction resulted in the (Z)-alkene and a chemoselective tosylation of the primary alcohol led to the formation of tosylate 5. This intermediate underwent a stereospecific 4-exo cyclization upon exposure to iodine

• epoxide was then opened by treatment with sodium azide and boric acid, yielding the azide derivative 146 in 87% from estrone. A subsequent reduction of the azide with LiAlH4 provided the aminoalcohol derivative 147 in 64% yield. Then, a chloroacetamido moiety was formed at the amino function in 51% yield

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

• , and subsequent reduction of the exomethylene at C11–C18 catalyzed by BscH yield brassicicene O (12). Renata and co-workers successfully accomplished the chemoenzymatic total syntheses of cotylenol (1) and nine brassicicenes (Scheme 3) [19]. In the cyclization phase, a suitably functionalized 5/8/5

• evolution using site-saturation mutagenesis targeting the putative active sites L110 and Y112, led to the variant MoBsc9 Y112M, which substantially improved the enzymatic conversion into 22, achieving an isolated yield of up to 67%. Diastereoselective reduction of the C8 ketone was then achieved using the

• protocol of Nakada and co-workers [27], enabling the chemo-enzymatic total synthesis of cotylenol (1). Similarly, diastereoselective reduction of the C8 ketone in 20 yielded the biosynthetic intermediate 8 for brassicicenes. Although substrate 8 has a different oxidation state at C8 and lacks the C9

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• known compounds, the generated GBB chemical space is unique as compared to the available compound collections. This fact is even more apparent from the t-distributed stochastic neighbour embedding (t-SNE) analysis, a technique widely used for the dimension reduction in data visualization [47]. Due to

• the relatively high computational costs of this method, we randomly selected 50,000 compounds to represent each database. The dimension reduction algorithm uses molecular features as the starting inputs to generate a few coordinates (in this case, t-SNE1 and t-SNE2) reflecting the probability of the

• (due to the large size of the dataset, a preliminary clusterization was performed to achieve ca. 5-fold size reduction); C) ZINC15 drug-like compounds, and D) enamine’s stock screening collection. Average T values are shown by dotted lines. t-Distributed stochastic neighbor embedding (t-SNE

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• nitrogen atmosphere, followed by reduction of the indole motif in compound 1n to indoline in 2n. The ester group in compound 2n was deprotected under basic conditions to give compound 3n (Scheme 2). DAn with different chain lengths of the alkyl linker were synthesized through an aza-Piancatalli

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• cyanoarenes, nitroarenes, quinolines, and pyridines using a proton-exchange membrane (PEM) reactor was developed. Cyanoarenes were then reduced to the corresponding benzylamines at room temperature in the presence of ethyl phosphate. The reduction of nitroarenes proceeded at room temperature, and a variety of

• anilines were obtained. The quinoline reduction was efficiently promoted by adding a catalytic amount of p-toluenesulfonic acid (PTSA) or pyridinium p-toluenesulfonate (PPTS). Pyridine was also reduced to piperidine in the presence of PTSA. Keywords: cyanoarene; nitroarene; PEM reactor; pyridine

• ; quinoline; Introduction Nitrogen-containing molecules are important bioactive compounds and intermediates in chemical synthesis. Therefore, the chemical transformations of nitrogen-containing compounds have been widely studied in the field of organic synthesis [1][2][3][4]. For instance, the reduction of