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

• 2022, Xu and co-workers established a site- and enantioselective cyanation of benzylic C(sp³)–H bonds using an electro-photochemical strategy (Figure 7) [55]. The reaction conditions show a broad substrate tolerance, and the late-stage functionalization of complex molecules derived from natural

• cyanation of benzylic C(sp3)–H bonds (Figure 7) [56]. A wide range of electron-poor and electron-rich alkylarenes 20 are suitable substrates for this electrophotocatalytic radical relay strategy. Additionally, late-stage functionalization of bioactive molecules provides the corresponding chiral cyanation

• important for more sustainable reactions. Furthermore, the application of electrochemical copper catalysis to complex molecules, such as for the late-stage functionalization of pharmaceuticals or materials and bioorthogonal functionalization of biomacromolecules, is necessary. Further advances in Cu

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• organic chemistry owing to their high bond dissociation energy compared to other aromatic C–X (X = Cl, Br, I) bonds [1][2][3][4][5][6][7]. This activation is essential for the late-stage functionalization of stable C–F bonds in complex molecules with reactive functional groups, providing an orthogonal

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• functionalization (LSF) of peptide scaffolds. α,β-Unsaturated amino acids like dehydroalanine (Dha) derivatives have emerged as particularly useful structures, as the electron-deficient olefin moiety can engage in late-stage functionalization reactions, like a Giese-type reaction. Cheap and widely available

• activation. The biocompatibility of the reaction enabled by the PBS solution and the mild photochemical reaction conditions makes the transformation useful for late-stage functionalization under physiological conditions. Besides, the reaction was successfully scaled up by roughly four times, leading to a

• Vergata” Via della Ricerca Scientifica, 1, 00133 Rome, Italy, Department of Chemical Sciences, University of Padova Institution, Via Francesco Marzolo, 1, 35131 Padova, Italy 10.3762/bjoc.20.271 Abstract The rising popularity of bioconjugate therapeutics has led to growing interest in late-stage

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

• , 52074, Aachen, Germany 10.3762/bjoc.20.214 Abstract With the resurgence of electrosynthesis in organic chemistry, there is a significant increase in the number of routes available for late-stage functionalization (LSF) of drugs. Electrosynthetic methods, which obviate the need for hazardous chemical

• representative examples to illustrate the potential of electrochemistry or photoelectrochemistry for the LSF of valuable molecular scaffolds. Keywords: electrochemistry; late-stage functionalization; paired electrolysis; pharmaceutical drugs; photoelectrochemistry; Introduction Organic electrochemistry is

• achieved compared to many classical methods. In light of the general trend towards more chemoselective protocols with broader functional group compatibility, there has been a growing interest in exploring the potential of electrosynthesis for the late-stage functionalization of complex scaffolds

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

• electric current. Both approaches can be considered as a late-stage functionalization; the easily available ortho-pyridyl-substituted diarylamines are used as the precursors. The direct approaches to N-arylpyridoindazolium salts elaborated herein open a route to broadening a scope of these practically

• -stage functionalization; easily available ortho-pyridyl-substituted diarylamines are used as the precursors. Keywords: anodic oxidation; diarylamines; electrochemical cyclization; pyridoindazolium salts; reversible ring closure; Introduction Aromatic polyfused N-heterocycles are of interest as a

• -pyridine substituted diarylamines, either using bis(trifluoroacetoxy)iodobenzene as an oxidant, or electrochemically, via potentiostatic oxidation. Electrochemical synthesis occurs under mild conditions; no chemical reagents are required except electric current. Both approaches can be considered as a late

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

• excellent yields (71–89%). Dömling et al. have used glyoxal dimethyl acetal as orthogonal bifunctional monoprotected aldehyde to synthetize GBB dimers as potential fluorophores. More details are given in chapter 5 [43]. The GBB reaction can be exploited also in the late-stage functionalization of natural

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

• using an enzyme or at what stage in a synthesis the enzyme is employed: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) the one-step construction of macrocyclic or fused multicyclic scaffolds via regio- and

• categorized into three distinct classifications based on the type of enzymatic conversions: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) one-step construction of macrocyclic or fused multicyclic scaffolds. This

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

• industry to implement such C–H transformations to diversify different types of molecules ranging from small drug-like molecules to intermediates and lead compounds. Especially late-stage functionalization is a promising emerging field that allows chemists to efficiently explore the chemical space in

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

• used to irradiate the reaction mixture to produce the desired product. The developed protocol was highly attractive as it eliminated waste generation, which was essential for practical use, particularly in late-stage functionalization. For the deoxygenation of primary substrates, which underwent slower

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent

• 1H-tetrazole as a bioisostere for carboxylic acid has long been recognized for its potential in enhancing drug-like properties [37]. Predominantly, tetrazoles are currently introduced by a late-stage-functionalization approach from their nitrile precursors. This work, however, takes an additional

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• the first reaction mode for a difunctionalization of alkenes with diazo compounds via a radical-polar crossover process. This synthetic transformation proceeds under mild reaction conditions and shows high functional group tolerance. The studies on late-stage functionalization, scale-up reactions, and

Selective and scalable oxygenation of heteroatoms using the elements of nature: air, water, and light

• Damiano Diprima,
• Hannes Gemoets,
• Stefano Bonciolini and
• Koen Van Aken

Beilstein J. Org. Chem. 2023, 19, 1146–1154, doi:10.3762/bjoc.19.82

• on the rate than acids and bases and both the anion and cation appear to influence the reaction kinetics. A deliberate choice of salt can either significantly improve the kinetics or quench the reaction. The latter might be exploited e.g., in late-stage functionalization strategies in order to

• applicability of the reaction conditions in a late-stage functionalization of APIs, the method was carried out on albendazole, and albendazole oxide (2t) was obtained with very good yield. Flow The photochemical protocol was then transferred to a flow setup in order to obtain a scalable and thus industrially

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• late-stage functionalization (17i and 17j) (Figure 12A). Interestingly, sodium oxalate could be used as the electron donor provided a catalytic loading of 4-cyanopyridine was added. Although the role of the latter species was not proposed by authors, it is more facile to reduce than an aryl chloride so

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• late-stage functionalization strategy [51][52][53] for the synthesis of natural products [42][54][55][56][57][58][59]. The goal of this review is to highlight and discuss the recent approaches for the synthesis of fluorinated derivatives by the direct incorporation of a fluorinated group of XRF type

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• following criteria: position/stage of the key cyclooctane ring formation in the synthesis plan, the selectivity, and the opportunity for late-stage functionalization. Review 1 Metathesis: ring-closing metathesis and related methods The metathesis reaction, first discovered by serendipity in the 1950s, has

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

•  32). It should be noted that other α-carbonyl CH bonds are not affected under these reaction conditions, which makes the method suitable for the late-stage functionalization of complex molecules. The method for selective remote CH-hydroxylation involving unactivated C(sp3)–H bonds employing

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• example of a very late stage functionalization of molecule would be the use of zinc sulfinate chemistry [297] which, as depicted here, allowed to introduce in one step a trifluoromethyl group on the hydroquinidine 47 and access the otherwise rather hard-to-get compound 48. In fact, CH functionalization is

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• , perfluorohexylation, and perfluorobutylation. Keywords: α-(perfluoroalkylsulfonyl)propiophenones; innate functionalization; late-stage functionalization; light-mediated perfluoroalkylation; perfluoroalkyl sulfinates; Introduction Perfluorinated compounds are a family of molecules containing a backbone where all C–H

• of these reagents as late-stage functionalization agents [26][27]. For a trend in reactivity, a more comprehensive scope of arenes and heteroarenes has been explored with the innate trifluoromethylation methodology previously reported by our group [10]. Conclusion In summary, we have successfully

• perfluoroalkylation of electron-rich aromatics, as well as in the late-stage functionalization of small molecules such as caffeine, which is of great interest in the current literature [28]. In future work, we will explore the reach and applicability of these reagents for the functionalization of compounds of

Earth-abundant 3d transition metals on the rise in catalysis

• Nikolaos Kaplaneris and
• Lutz Ackermann

Beilstein J. Org. Chem. 2022, 18, 86–88, doi:10.3762/bjoc.18.8

• , Germany 10.3762/bjoc.18.8 Keywords: C–H activation; 3d transition metals; green chemistry; late-stage functionalization; sustainability; Transition metal catalysis has emerged as a transformative platform for the assembly of increasingly complex compounds, with enabling applications to natural product

• . Applications of this strategy range from late-stage functionalization to modern photocatalysis and electrocatalysis, with contributions from around the globe, including Brazil, China, Japan, Germany, India, and South Korea, among others. The increasing use of C–H activations in academic and industrial

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• applicability in late-stage functionalization. The Bao group has since demonstrated many other carbon-centered radicals were amenable in the carboazidation reaction of alkenes including diacylperoxides [133] and aldehydes [134]. In 2021, the Bao group followed up on their previous work and developed an

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• . The photo-electro methodology allowed the late-stage functionalization of valuable bioactive molecules, and the structures of a adapalene precursor (65) and ibuprofen derivative (66) were successfully azidated in moderate yields (Scheme 23C). Some silylated compounds like 67 have proven to be

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• biologically active small molecules and complex peptides. Keywords: bioactive molecules; 3d transition metals; late-stage functionalization; manganese catalyst; sustainable catalysis; Introduction Manganese, a 3d transition metal, allows for a potentially ideal sustainable catalytic system because of the

• assistance. However, application of this protocol for late-stage functionalization remains challenging [96][97][98][99][100][101][102][103]. In 2021, it was revealed by the Ackermann group that manganese(I) catalysis enabled the bioorthogonal late-stage alkenylation of structurally sophisticated peptides

• -containing peptide 37g. Conclusion Metal-catalyzed late-stage functionalization has shown significant potential in the fields of medicinal chemistry, agrochemistry, and chemical biology. While transition metal catalysis has been a reliable and efficient strategy for late-stage functionalization, it suffers

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• : benzhydrazides; copper; 3-methyleneisoindolin-1-one; removable directing group; Introduction Inexpensive copper-promoted oxidative C−H activations [1][2][3][4][5][6][7][8][9][10][11] have been recognized as competent tools for the efficient assembly and late-stage functionalization of organic molecules due to

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• substrates (Scheme 2 and Scheme 4), and an external proton source (acetic acid) was required to furnish the hydroalkylated products 7 (Scheme 5A). The quaternary carbon centers were synthetized in moderate to excellent yields by this methodology, and its potential use in late-stage functionalization was

• methanol and gentle heating was necessary to optimize the formation of 75 from 74. As is usual in these Mukaiyama-like reaction conditions, the developed hydromethylation tolerated an array of functional groups and the late-stage functionalization of complex natural products (75e–g). Deuterated and other