Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• -yield products were obtained when two methyl groups were positioned at the para or meta positions. The evaluation of the synthetic potential of the C−P bond formation revealed that the cleavage of the C−H bond in thiophene likely does not participate in the rate-determining step. Based on the

• and the overall structure of the complex highly influence the oxidation potential of Pd(II). At first, a complex of phenylpyridine with palladium (including insertion of Pd to C–H bond) and dialkyl phosphonate was formed, followed by anodic oxidation to give the final coupling product. In 2023, Zhou

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• polar C–F bonds at the end of an alkyl chain, is that the terminal C–H bond also becomes polarised. In the case of the difluoromethyl group, the terminal hydrogen bears a partial positive charge and is able to act as a H-bond donor (II, Figure 2). This can influence the conformation of the molecule if

• rotamers have different energies. When the C–F bonds are aligned gauche, the vacant σ* orbital of each C–F bond is able to mix with the filled σ orbital of an adjacent C–H bond, and this hyperconjugative interaction stabilises the gauche conformer (III, Figure 2). The anti conformer does not benefit from

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• observed by LC–MS when the electrolysis was performed in 5:1 MeCN/D2O (Scheme 2, reaction 2). The considerably higher O–H bond dissociation energy (119 kcal/mol) [12] as compared to that of the C–H bond in MeCN (86 kcal/mol) [13] renders the hydrogen atom abstraction from water by a carbon-centered radical

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• (DMF), dimethyl sulfoxide (DMSO), or dioxane to achieve high yields. The assumed mechanism is initiated by activation of the C–H bond of the terminal alkyne by a metal catalyst. The resulting metal acetylide reacts with the imine/enamine through a nucleophilic addition. Because imines/enamines are

• to the AAA coupling, except for iron, where the temperature must be increased to 100 °C. This can be explained in terms of the activation of both the C–H and C–X bonds by metal catalysis, which is not the case in AAA couplings, where only the C–H bond is activated, making the last step (nucleophilic

• between 60–95% for all metal catalysis conditions. The most widely accepted mechanism is as follows: the alkynyl C–H bond is activated by the metal catalyst (Scheme 23). The metal can be added in its proper oxidation state (such as Cu(I)) or generated in situ (as in the case of Au(I), Co(I), Fe(II) and Ni

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• reveal the fundamental differences between the C–H bond and the O–H bond as HB donors and provide important quantitative information for applying the CF2H group as an OH group mimic. We next attempted to establish correlations of experimentally determined HB donation ability, in terms of Kd or ΔGexp

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• with a newly formed C–H bond. These radical species then enter the second catalytic cycle, facilitating the asymmetric cyanide transfer. The radical species 93 undergo a single oxidative addition to the Cu(II)–CN catalyst 96, forming a Cu(III) complex. Finally, reductive elimination delivers the

Intramolecular C–H arylation of pyridine derivatives with a palladium catalyst for the synthesis of multiply fused heteroaromatic compounds

• Yuki Nakanishi,
• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2024, 20, 3256–3262, doi:10.3762/bjoc.20.269

• Abstract The C–H arylation of 2-quinolinecarboxyamide bearing a C–Br bond at the N-aryl moiety is carried out with a palladium catalyst. The reaction proceeds at the C–H bond on the pyridine ring adjacent to the amide group in the presence of 10 mol % Pd(OAc)2 at 110 °C to afford the cyclized product in 42

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• catalytic cycle. A Pd-catalyzed synthesis of di-tert-butylperoxyoxoindole derivatives 210 from acrylic acid anilides 209 and TBHP was developed (Scheme 65) [134]. The authors proposed that the initially formed diperoxide A undergoes electrophilic attack by cationic Pd(II) on an aromatic C–H bond with the

• -peroxyamides 148 with TBHP and formamide derivatives 147 by difunctionalization of 1,3-diene, 1,3-enynes as well as styrenes 146 (Scheme 46) [110]. The iron catalyst is believed to mediate the formation of tert-butoxy and tert-butylperoxy radicals. The former abstracts the hydrogen atom from the formyl C–H

• bond, revealing the amino acyl radical, which is then added to the double bond. Tetra-n-butylammonium bromide (TBAB)-catalyzed carbonylation–peroxidation of styrene derivatives 149 with TBHP and aldehydes 150, which allows for the synthesis of β-peroxy ketones 151, was described (Scheme 47) [111]. tert

C–H Trifluoromethylthiolation of aldehyde hydrazones

• Victor Levet,
• Balu Ramesh,
• Congyang Wang and
• Tatiana Besset

Beilstein J. Org. Chem. 2024, 20, 2883–2890, doi:10.3762/bjoc.20.242

• ). Mechanistic investigations revealed that AgSCF3 was the active species in the transformation. Keywords: C–H bond functionalization; C–S bond formation; hydrazones; synthetic method; trifluoromethylthiolation; Introduction Fluorinated molecules are of paramount importance [1][2][3][4][5][6][7][8][9][10][11

• towards trifluoromethylthiolated hydrazones will be the direct C–H functionalization of the corresponding aldehyde hydrazone, an uncharted transformation to date. Forging a C–S bond by the direct C–H-bond functionalization of hydrazones is still underdeveloped. Except for transformations leading to the

Transition-metal-free synthesis of arylboronates via thermal generation of aryl radicals from triarylbismuthines in air

• Yuki Yamamoto,
• Yuki Konakazawa,
• Kohsuke Fujiwara and
• Akiya Ogawa

Beilstein J. Org. Chem. 2024, 20, 2577–2584, doi:10.3762/bjoc.20.216

• with halogen or triflate groups. Recently, transition-metal-catalyzed direct borylation of arenes via C–H bond activation has been reported, although the design of the substrate and ligands is somewhat complicated [16][17][18][19][20][21][22]. Since the complete removal of catalyst-derived metal

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

• been systematically summarized, classifying them by targeted C–H bond functionalization and the newly formed bonds [4][5]. In this review, we aim to provide a comprehensive classification and overview of the currently available electrochemical and photoelectrochemical methods for the LSF of

• in schemes as H2↑) in the cathodic half-reaction, which will however not be addressed in greater detail in this review. 1.1 Direct anodic oxidation of substrates 1.1.1 C–H bond functionalization. C–H bond carbofunctionalization: CF3 groups can be installed on heteroarenes at a late stage via a TM

• bioactive compounds such as caffeine and prothioconazole (Scheme 2a). Additionally, Lin, Terrett and Neurock's group [8] reported the electrochemical C(sp3)–H methylation of complex molecules. This strategy enabled the synthesis of the "magic methyl" product, a TRPA1 antagonist (Scheme 2b). C–H bond

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

• this position was thought a reasonable approach to extend drug t1/2 through exploitation of the kinetic isotope effect underpinned by the C–D bond being slightly shorter and stronger than a C–H bond. Such site-specific labeling was hypothesized to slow CYP3A4 metabolism. To evaluate the hypothesis

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

• complex molecules by exchanging a C–H bond with different functional groups to modify the biological activity of drugs [2]. However, pinpointing which C–H bond is reacting can be challenging. Grzybowski and co-workers recently addressed this gap by predicting pKa values for C–H bonds in dimethyl sulfoxide

• 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

• . Furthermore, we employ our model on 1043 pKa-dependent reactions (aldol, Claisen, and Michael) and successfully indicate the reaction sites with a Matthew’s correlation coefficient (MCC) of 0.82. Keywords: C–H pKa values; pKa predictor; Introduction Over the years, the ability to selectively break a C–H

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• for the efficient monofluorination of 4- and 2-alkylpyridines (Figure 4 – conditions [A]) [36]. The transformation relied on the polarisation of the heterobenzylic C–H bond, via the intermediate formation of an N-sulphonylpyridinium salt, to promote deprotonation. Following a polar mechanism with

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• -state *[Ir(III)] complex can effectively oxidize the nitrogen atom of activated NHC–alcohol adduct 66 via SET. The resulting nitrogen radical cation intermediate 67 weakens the adjacent C–H bond, making it more acidic and susceptible to deprotonation by a suitable base, ultimately yielding an α-amino

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• isolated product was an indol-3-one derivative (Scheme 14). Another example for the synthesis of 3-substituted indoles was described by Hsieh and Dong [35]. They synthesized 3-arylindoles by palladium-catalyzed C–H bond amination via reduction of nitroalkenes using carbon monoxide as reducing agent. The

• palladium-catalyzed reductive N-heteroannulation. Synthesis of 3-arylindoles by palladium-catalyzed C–H bond amination via reduction of nitroalkenes. Synthesis of 2,2′-bi-1H-indoles, 2,3′-bi-1H-indoles, 3,3′-bi-1H-indoles, indolo[3,2-b]indoles, indolo[2,3-b]indoles, and 4,4′-diaza-3,3′-bi-1H-indole. Pd

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• advantage, facilitating the formation of two or more chemical bonds in a step-economic manner [9][10][11][12][13]. In a prior study, we reported a palladium-catalyzed efficient activation of both C–I bond and the adjacent C–H bond of diaryliodonium salts in the formation of 4,5-benzocoumarin derivatives

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• ) [78]. Another advantage of the MH HAT process is that the α-C–H bond in the corresponding radical is comparatively stable, whereas a carbocation has superacidic α-C–H bonds with a pKa of ≈ −17 [79]. Therefore, polar hydrochlorination reactions are in competition with elimination reactions which is not

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• position of quinazolines requires longer time, higher temperatures, and sometimes the use of expensive transition-metal catalysts [12]. A selective C2 modification can be achieved by using 2-chloroquinazolines IV, where the C4 position is blocked by an unreactive C–C or C–H bond (Scheme 1). Cyclization

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• palladium-catalyzed direct intermolecular arylation, followed by a direct intramolecular arylation step. As the C–H bond activation of several benzene derivatives remains very challenging, the preparation of fluoranthenes from 1,8-dibromonaphthalene via Suzuki coupling followed by intramolecular C–H

• activation has also been investigated to provide a complementary method. Using the most appropriate synthetic route and substrates, it is possible to introduce the desired functional groups at positions 7–10 on fluoranthenes. Keywords: catalysis; C–H bond functionalization; direct arylation; fluoranthenes

• using commercially available substrates and allowing the regioselective introduction of functional groups at the desired positions is still needed. By using Pd-catalyzed double C–H bond functionalization of activated arenes, such as (poly)fluoroarenes, or by combining a palladium-catalyzed

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• of quinoquinolines, their planar structure, and very easy coordination to acidic and electrophilic sites (including water [15][22] or the C–H bond of chloroform [11]) almost always lead to co-crystallization. For example, there is no such crystallographic information for quinoquinoline 3 itself. In

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• catalyst for obtaining the product of insertion into the NH bond of the heterocycle. An effort to obtain the N–H insertion product with dibenzoazepine proved fruitless. Instead, the product of insertion into the C–H bond of the activated benzene ring (9z) was isolated in moderate yield. The chemo- and

C–H bond functionalization: recent discoveries and future directions

• Indranil Chatterjee

Beilstein J. Org. Chem. 2023, 19, 1568–1569, doi:10.3762/bjoc.19.114

• Indranil Chatterjee Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab 140001, India 10.3762/bjoc.19.114 Keywords: C–H bond functionalization; The process of C–H bond functionalization can be defined as the replacement of an activated or nonactivated C−H

• the abstraction of intramolecular hydrogen atoms. Radical chemistry is a viable alternative to the two-electron process, involving C–H bond functionalization in the absence of any ligand and using low-cost redox-active metals (Fe, Cu, Mn, etc.) rather than heavy metals (Rh, Ir, etc.). Although radical

• its combination with organometallic chemistry for site-selective C−H bond functionalization [3][4]. Recent years have witnessed many viable strategies for the synthesis of complex targets utilizing photoredox catalysis, electroorganic catalysis, Lewis acid catalysis, and transition-metal-free

Lewis acid-promoted direct synthesis of isoxazole derivatives

• Dengxu Qiu,
• Chenhui Jiang,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2023, 19, 1562–1567, doi:10.3762/bjoc.19.113

• developed to prepare isoxazole derivatives [10][11][12][13]. However, most of the starting materials for these methods are oximes and hydroximinoyl chlorides [4][13][14][15]. Recently, the sp3 C–H bond functional group transformation of 2-methylquinoline derivatives into isoxazole derivatives has been

• the Lewis acid to realize the sp3 C–H-bond activation of nitrogen heterocycles to synthesize isoxazole derivatives. Results and Discussion At the outset of this study, we chose the reaction of 2-methylquinoline (2a) with phenylacetylene (1a) in the presence of AlCl3 (3 equiv) and sodium nitrite (10

• oxide E [23], which can be converted to the desired isoxazole with 1a through a 1,3-dipolar cycloaddition. Conclusion In conclusion, we have developed an efficient and concise synthesis of isoxazole nitrogen heterocycles by direct C–H-bond activation of methyl heteroaromatics. The method avoids using

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• this work. In 2018, Anbarasan and Chaitanya developed an efficient approach for the C–H bond functionalization of aryl compounds containing a directing group using N-(thioaryl)phthalimides 14 in the presence of a palladium catalyst (Scheme 15) [53]. The thiolation occurred in the presence of Pd(OAc)2

• substitution to provide C2,C3-disulfenylated product 66 (Scheme 28). In the same year, Sutherland and Dodds disclosed a protocol for the C–H bond thioarylation of electron-rich arenes 4 like anisoles, acetanilides, phenols, and N-heterocycles in the presence of Fe(III) Lewis acid and ionic liquid [BMIM]NTf2 as