A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• -free electrochemical method. This route was reported in 2014 by the Baran and Blackmond groups [6]. A commercially available reagent, Zn(SO2CF3)2, was used as the CF3 radical source in the reaction. Additionally, a series of substrates could be difluoromethylated under the reported electrochemical

• agrochemical and pharmaceutical chemistry. In 2019, Jiao and colleagues reported that 1,2-dichloroethane (DCE) could be used as a chlorination reagent for the production of (hetero)aryl chlorides and vinyl chlorides [21]. The reactions were carried out in an undivided cell containing a mixture of DCE in

• oxidation strategy to obtain α-chlorosulfoxides from sulfides using hydrochloric acid as a bifunctional reagent [22]. This strategy accommodates a broad range of substrates and offers high diastereoselectivity and regioselectivity. Several LSF modifications of amino acids and pharmaceutical derivatives

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• rigorously verify the compatibility of each solvent and reagent combination used in reactions and eliminate any potential hazards [218]. Second, in terms of algorithmic approaches, the widely used BO requires initial data to build a probabilistic surrogate model. Although the data might be sourced from

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• ]. Iodoethane was also shown to be an effective reagent furnishing the product in up to 56% upon heating to 40 °C (Table 1, entries 11 and 12). It was envisaged that oxidation of iodoethane led to formation of oxidized forms of iodide by C–I-bond cleavage, therefore tetrabutylammonium iodide was utilized to see

• if the result could be replicated and it was (Table 1, entry 13). Finally, the reaction was shown to occur using PIFA (bistrifluoroacetoxyiodobenzene), which is envisaged to be produced in the reaction mixture when using iodobenzene as reagent, and a similar yield was obtained (Table 1, entry 14 vs

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• -to-handle reagent, NaOCl·5H2O. Because very little has been disclosed about the reactivity of such 2,3-epoxyesters, their epoxy ring opening by a variety of nucleophiles was carried out and we succeeded in clarifying these chemo- as well as regioselective processes proceeding via the SN2 mechanism to

• synthesis to get access to the synthetically quite useful compounds like 2a [33][34]. Under such situations, we envisaged that the high electrophilicity of compound 1a would permit the usage of the extraordinarily convenient and mild reagent NaOCl [35][36][37][38] which opens the promising route for the

• (entries 3 vs 1 and 2). The drawback of this sequence was the isolated yield of 2b no more than 70% which was, at least in part, due to the production of the undesired hydrolyzed products from 1b and/or 2b under the alkaline conditions of this epoxidation reagent. This was experimentally proved by the

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• serve as guidance for industrial production. Experimental Materials and methods Chemicals O-Methylisouronium sulfate (IO, 95%) was purchased from Shanghai Yien Chemical Technology Co., Ltd; fuming nitric acid (HNO3, 98.0%) was purchased from Sinopharm Chemical Reagent Co., Ltd.; sulfuric acid (H2SO4

• , 98.0%) was purchased from Sinopharm Chemical Reagent Co., Ltd.; pure water from AR, Hangzhou Wahaha Group Co., Ltd.; all reagents were used without further purification. Sulfuric acid solutions of different mass fractions were prepared with pure water and 98% concentrated sulfuric acid in an ice bath

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• attributed to the chair-like transition state where the organoboron reagent 1 exchanges one isopropoxy group for one of the BINOL 3 oxygen atoms, whereas the free OH group of the BINOL forms a hydrogen bond to the carbonyl of substrate 2. The flanking phenyl groups on the BINOL facilitate recognition between

• highly enantioselective nucleophilic addition of primary (10), secondary, and even tertiary allylboronates, as well as allenylboronates to a broad set of imines, bearing the N-phosphinoyl group. The new approach allowed the activation of both the substrate and the reagent using aminophenol organocatalyst

• -imine is activated either with a Brønsted or Lewis acid. In both cases, the allyl group of the silane reagent 46 attacks from the Re-face of the imine, leading to the major (R)-enantiomer of 47. Based on the experimental data obtained with the preformed silylated catalyst and preformed imine, the Lewis

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• extended this approach to amides 5 containing a furazan ring that were obtained via the reaction of readily available 4-amino-3-furazancarboxylic acid 6 with various amines using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) as a coupling reagent (Scheme 3; see Supporting

• additionally confirmed by X-ray diffraction (see Supporting Information File 1 for details) (Figure 2). To confirm the reaction mechanism, we performed diazotization followed by azo coupling of amide 2a using labeled Na15NO2 as the nitrosating reagent (Scheme 4). As a result, 15N-labeled triazinone 8 was

• conducted a series of studies. Thus, due to the presence of a furoxan fragment, triazinones 1 can act as NO-donors. To assess their NO-release capability, compounds 1 were kept for 1 hour under physiological conditions (pH 7.4, 37 °C), then Griess reagent was added and studied by spectrophotometry (this

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• [84][85]. Similar to the DMP-tag, the AzidoTMT introduced by Ma et al. contains an azide to selectively label probe–peptide conjugates, but the synthesis takes advantage of the commercially available isotopically labeled 11plex-TMT (Figure 7B) [82]. The 11plexTMT reagent is reacted in one step with 3

• beads, the beads can be split into two portions from which one is analyzed by in-gel analysis first to determine the overall labeling and the other portion after on-beads trypsin digest is subjected to LC–MS/MS analysis. The AzKTB reagent can be synthetized by standard solid-phase peptide synthesis

• or scale down and partially automatize the protocol or both. The standard mass spectrometry-based chemical proteomics workflow requires up to 1 mg of total protein, acetone protein precipitation after the ‘click’ reaction to remove the excess of the biotin-containing reagent, desalting of the

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

• ), Koser’s reagent (PhI(OH)OTs), Zhdankin’s reagent (C6H4(o-COO)IN3, ABX), and Dess–Martin periodinane (DMP) – and find application in an array of synthetically important transformations including olefin difunctionalization, carbonyl desaturation, alcohol oxidation, and C–H functionalization [3][4

• with the stability of the relevant iminoiodinane reagent, with higher yields attributed to more electron-rich sulfonamide substitution such as 2a. Relatively electron-deficient iminoiodinanes are less efficient but are also more prone to decomposition (see Supporting Information File 1, Figure S2 for

• , signaling the binding of HFIP to 2c enhanced the electron transfer kinetics between the hypervalent iodine reagent and the electrode [45]. Further additions of HFIP further increased the current response and shifted the peak potential, with 10 µL and 15 µL of HFIP showing responses with Epr at −1.55 V and

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

• [96] investigated a bromocyclization catalysed by a chiral phosphoric acid (CPA) and a DABCOnium brominating reagent (Figure 6). The authors calculated transition state conformer ensembles for several flexible DABCOnium systems and performed energy decomposition analysis to separate the interactions

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

• flexibility [8]. Indeed, early incorporation of deuterium during hit generation may negate the need for late-stage C–H functionalization which often requires strong external oxidants or affords products with significantly lower biological activity [25][26][27]. Thus, eight MCRs were evaluated for D-reagent

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

• the use of HF or its complexes as a reagent. These reactions seem to proceed via the formation of the vinyl fluoride as the intermediate [25][26][27][28]. In the first example, Olah and co-workers reported the reaction of terminal alkynes with HF/pyridine (Olah reagent) (Figure 1, reaction 1) [29][30

• to be a good reagent for the gem-difluorination of alkynes, reported by Hammond and Xu (Figure 1, reaction 3) [37]. HF/DMPU is easy to handle under experimental conditions. In addition, they recently reported the utilization of a combination of KHSO4·13HF and DMPU·12HF under neat conditions for the

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

• to the DAntM radical is shown in Scheme 1. The alcohol precursor 3 was prepared via addition reaction of lithium reagent 2 to 10-mesitylanthracene-9-carbaldehyde (1) in moderate yield (59%). The generation of the DAntM radical was performed using stannous chloride dihydrate with hydrogen chloride in

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

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

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

• is a promising synthetic reagent not only as a one-carbon homologation reagent but also as a nitrogen source for nitrogen-containing molecules. Because of their isoelectronic structure with carbon monoxide, isocyanides also react with nucleophiles, electrophiles, carbon radicals, and transition metal

• reaction, pressurization in an autoclave or other pressurization device is required to increase the CO concentration. Isocyanides, on the other hand, have an isoelectronic structure with carbon monoxide and are expected to be not only a promising C1 resource but also an important synthetic reagent for

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

• conditions, a significant amount of degradation products was observed and the yield was rather low. The same result was obtained when the reagent was first added at 0 °C and then heated for one hour under microwave irradiation (Table 1, entry 2). To avoid degradation, the temperature was reduced while the

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• substrates according to this method. However, attempts to carry out the reaction sequence with unprotected hydrazine were unsuccessful. Alternatively, Mitsunobu reagent 23 can be reacted with in situ generated benzyne (from o-(trimethylsilyl)phenyl triflate) to provide the hydrazides for the concomitant

• one-pot process (Scheme 43) [140]. This alkynone generation fulfills two functions: on the one hand, it acts as an activating reagent in the coupling reaction and, on the other, as a ring-forming component. Notably, this process can only be carried out as a domino reaction. For the coupling of

• )-cycloaddition of nitrile oxides 137, generated in situ from hydroxyiminoyl chloride 135 and terminal alkynes, was proposed by Kovacs and Novak. Copper supported on iron serves as a catalyst and as a reagent for the reductive ring opening and leads to β-aminoenones 139, which react in the consecutive one-pot

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

• appealing opportunities to take advantage of the versatility of this reagent. Such an approach can either ameliorate the previous methods in a more sustainable and efficient fashion or provide a mean for the discovery of new reactivity. Herein, this review aims to give an overview of the state of the art in

• the aromatic product 85, thereby regenerating the catalyst (Scheme 16) [61]. Given its abundance, stability, and low price, elemental sufur (S8) is an ideal source of sulfur atom to produce thiacycles [62]. In 2019, H.-T. Tang utilized this reagent in combination with (hetero)aromatic ketone-derived

• two carbone graphite electrodes. The Togni reagent 127 was chosen as a source of trifluoromethyl radical with redox neutral and electron-rich hydrazones through a paired electrolysis. In contrast, the Langlois reagent 128 was preferred for electron-poor substrates through an electrooxidative process

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

• -dimethylaminopyridine (DMAP) and triethylamine. Used as a model system, the subsequent reaction of sulfonate 12 with compound 6 under varied conditions afforded products P1 and P2. We investigated effects of reagent stoichiometry, bases, reaction time, and temperature on the yields of product P1, as summarized in Table

• yields from the same carbon sources through reagent control. Experimental General methods All materials were obtained from commercial suppliers and used without further purification unless otherwise noted. Anhydrous solvents were obtained from Sigma-Aldrich and used directly. Reactions involving air- 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

• of ethyl 2-bromoacetate through a pre-activated zinc column (see page 11 in Supporting Information File 1) [44]. The Reformatsky reagent could be obtained in yields varying from 70 to 90% depending on the activation state of the column. The yield of the reaction was determined by titration with

• within 4 h in the dark, irradiation with blue light halves the reaction time for many compounds. Overall, these observations are in line with those of Alcazar et al. [43]. In their work, the authors demonstrated the formation of a complex between palladium and the organozinc reagent which is absorbing in

• protection of the aromatic NH group (2s vs 2t; 2v vs 2u). Reactions with unprotected imidazoles 1s and 1v led to immediate formation of a precipitate upon addition of the Reformatsky reagent. Surprisingly, 1z did not afford the expected product (2z). The synthesis of the Reformatsky reagent can be combined

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

• isoquinolinone derivatives. The method provides highly chemoselective access to 3- or 4-substituted isoquinolinone derivatives by reacting o-alkenylbenzamide derivatives with PISA in either acetonitrile or wet hexafluoro-2-isopropanol. Keywords: annulation; C–H amination; hypervalent iodine reagent; iodine(III

• option for the preparation of isoquinolinone derivatives. In 2020, two reports have been published on the conversion of alkyne-tethered N-alkoxybenzamides to isoquinolinones by intramolecular oxidative annulation, either electrochemically or using the hypervalent iodine reagent phenyliodine(III

• zwitterionic water-soluble hypervalent iodine reagent (phenyliodonio)sulfamate (PISA). In water, PISA is strongly acidic, and the pH value can reach 2.05 in a saturated aqueous solution. With PISA, various indoles have been synthesized via C–H amination of 2-alkenylanilines involving an aryl migration

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

• amine oxidation is increased. Electrochemical synthesis of pyridoindazolium salts The results of the voltammetry testing allowed to assume that pyridoindazolium salts can also be obtained using an anodic synthesis. Electric current as a reagent is inherently safe and easily scalable; electrosynthesis is

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• ; reaction scale – 0.25 mmol; ascaled-up (1.5 mmol) yield. Negative results with several N-, O-, and C-nucleophiles and with diazo reagent 1m. Preparation of acids 4 by hydrogenolysis of benzyl esters and examples of acid 4a amidation. Supporting Information Deposition Number CCDC 2323689 (for 3t) contains

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

• (controlled pore glass). In this study they used a benzaldehyde unit conjugated to a hexathymidine oligonucleotide 39 and reacted it with various isocyanides and amidines to obtain a small collection (9 examples) of adducts 40 in yields ranging between 23% and 95%; large excess of reagent and a weak Brønsted

• derivative because the base properties of the reagent could hinder AcOH from catalyzing the reaction. Smith et al. [54] explored the potential of acyclic amidines 54 in the synthesis of substituted-imidazoles via the GBB reaction under MW heating (Scheme 21). The resulting 5-aminoimidazoles 55 were in situ