Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• were explored, using a total volume of 4.5 mL reaction mixture, and the screening results can be readily translated to continuous flow synthesis. The application of segmented flow or microslug reactors was demonstrated in the decarboxylative arylation cross-coupling reaction promoted by catalysts and

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• %). This cascade involves an initial Suzuki–Miyaura cross-coupling reaction between 1,8-dihalonaphthalenes and heteroarylboronic acids or esters, followed by an intramolecular C–H arylation under the same conditions to yield the final heterocyclic fluoranthene analogues. The method was further employed to

• total synthesis of the fungal natural product bulgarein. Keywords: acenaphthylene-fused heteroarenes; benzo[j]fluoranthenes; C–H arylation; fluoranthenes; heterocycles; Introduction An important subclass of polycyclic aromatic hydrocarbons (PAHs) [1] is comprised of fluoranthenes, which have been the

• -based natural product, which was discovered to induce topoisomerase I-mediated DNA cleavage [16][17]. For the construction of the fluoranthene skeleton, a broad range of synthetic strategies including C–H arylation [18][19][20][21][22], Diels–Alder [7][8][23][24][25] and [2 + 2 + 2] cycloadditions [26

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

• by Chatgilialoglu et al. [22] under non-photoredox conditions, MacMillan et al. [23] sparked renewed interest in silanes as XAT reagents by generating a tris(trimethylsilyl)silyl radical through photoredox catalysis for arylation reactions [22][23]. In 2018, Balsells et al. [24] reported a similar

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

• % yield, respectively. The related reaction is also carried out with amides of non-pyridine derivatives terephthal- and benzamides to afford multiply fused heterocyclic compounds in 81% and 89% yields, respectively. Keywords: intramolecular C–H arylation; multiply fused heterocycles; palladium acetate

• ; phosphine ligand; pyridine amides; Introduction Transition-metal-catalyzed synthetic reactions have recently attracted much attention in synthetic organic chemistry [1][2]. C–H Arylation reactions catalyzed by a transition metal are of particular interest because these reactions involve rather superior

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• research groups recently reported the α-arylation between sulfoxonium ylides and diaryliodonium salts [33], and encouraged by this precedent, we envisioned that the chemistry between sulfoxonium ylides and hypervalent iodine compounds might be ripe for further exploitation. The trifluoroethyliodonium salt

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• the synthesis of cyclic imines using a one-pot protocol involving Grignard addition to a cyano group followed by PhI(OAc)2 (Scheme 30) [51]. The authors used p-tolylmagnesium bromide for both the arylation of the unsaturated carbonitriles 55 and as a bromide source. Bromocyclisation was achieved using

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• at β- and meso-positions, N-alkylation, arylation or protonation, interruption of the conjugated system, reduction/oxidation of the macrocycle and/or strapping of the macrocycle via covalent linkage of the meso- or β-pyrrole positions [22][53][54][55][56][57]. These alternations can significantly

• metal-free macrocycles for the C–H arylation of five-membered heteroarenes using aryldiazonium salts, with porphyrin serving as the photoredox catalyst [92]. Control experiments indicated that H2TPP (18), when irradiated with light, gave 80% yield of the C–H arylated product 77 for the reaction of furan

• the electrochemical and photochemical properties of the catalyst was crucial for facilitating photoelectron transfer (PET) processes in these photoredox systems. De Oliveira and co-workers reported metal-free porphyrins as photoredox catalysts for the synthesis of α-arylketones/aldehydes by arylation

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• concentrate on various arylation reactions involving carbon and other heteroatoms, encompassing rearrangement reactions in the absence of any metal catalyst, and summarize advancements made in the last five years. Keywords: arylation reaction; diaryliodonium salts; electrophilic arylation reagent; metal-free

• arylation; rearrangement reaction; Introduction The chemistry of hypervalent iodine compounds is well-established and they are prevalent as oxidants and electrophilic reagents in organic conversions [1][2][3]. They have gained significant attention due to their high reactivity and ability to carry out

• , diaryliodonium salts (DAIS), a versatile category of hypervalent iodine compounds, have seen significant progress in hypervalent iodine chemistry. Their efficiency and environmentally friendly characteristics have positioned DAIS as next-generation arylation reagents [29][30]. Other than aromatic electrophiles

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

• AgSCF3. Finally, to further illustrate the synthetic utility of the trifluoromethylthiolated hydrazones, product 2g was further functionalized. In the presence of 4-methylboronic acid, the arylation of 2g occurred and the expected product was isolated in 72% yield with the SCF3-hydrazone motif remaining

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• , many of these strategies are utilized only with planar porphyrins. Apart from the arylation of the β-position of 2,3,5,7,8,10,12,13,15,17,18,20-dodecaarylporphyrins, developed by Smith and co-workers [39] few reports on synthetic techniques for dodecasubstituted nonplanar porphyrins can be found in

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• and rearomatization. Arylation by alkynylcopper driven dearomatization and rearomatization. Remote substitution/cyclization/1,5-H shift process. Proposed mechanism. Arylation or amination by alkynylcopper driven dearomatization and rearomatization. Remote nucleophilic substitution of 5

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

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• desired meta-heterocycle aniline 3ag was prepared in low yield. Finally, the developed method is suitable for the late-stage arylation of drug-like molecules such as deacetyllinezolid (3ak). The meta-substituted anilines 3 are formed in a sequence of reactions shown in Scheme 6 [53]. Firstly, the reaction

A new platform for the synthesis of diketopyrrolopyrrole derivatives via nucleophilic aromatic substitution reactions

• Vitor A. S. Almodovar and
• Augusto C. Tomé

Beilstein J. Org. Chem. 2024, 20, 1933–1939, doi:10.3762/bjoc.20.169

• or novel properties can be prepared by conventional chemical modifications of simple DPP derivatives [3][18]. The most frequently used transformations include: i) N-alkylation with adequately functionalized alkyl groups [19][20][21][22], ii) N-arylation [23][24][25], and functionalization at the 3,6

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

• range of less widely applicable strategies have been developed as well [17][18][19][20][21][22]. The above-mentioned methods focus on the synthesis of α-alkyl-amino acids. Moving to α-aryl-amino acids, the Clayden group published an excellent asymmetric α-arylation method to access quaternary amino

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

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

• substrates [7][8]. Pre-functionalized arenes are essential precusors in all of these general approaches. 2-Cyclohexenones are fundamental and versatile organic synthetic materials [9][10]. They have been applied as an ideal arylation platform to construct functionalized anilines via an amination

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

• –halogen bond formation, as well as C–H functionalization [27]. Some notable examples include C–H arylation, various cross-coupling reactions, oxidative coupling, and photocatalytic radical reactions. The advantages of visible-light-induced photoredox catalysis are due to the ability to utilize visible

• bond activation of benzyl alcohols. Deoxygenative arylation of alcohols using NHC to activate alcohols. Deoxygenative conjugate addition of alcohol using NHC as alcohol activator. Synthesis of polysubstituted aldehydes. Funding The author thanks SERB, India (CRG/2021/000402) for financial assistance.

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• the additional electron transfer to form the corresponding anions is a highly favorable pathway due to the more positive reduction potential of radicals than that of the starting halides [38], employing redox mediators enables the generated aryl radicals to participate in radical arylation reactions

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis

• Johannes Rocker,
• Till J. B. Zähringer,
• Matthias Schmitz,
• Till Opatz and
• Christoph Kerzig

Beilstein J. Org. Chem. 2024, 20, 1236–1245, doi:10.3762/bjoc.20.106

• catalyst in the sulfonylation/arylation of styrenes and as a triplet sensitizer in energy transfer catalysis. The singlet lifetime is sufficiently long to exploit the exceptional excited state reduction potential for the activation of 4-cyanopyridine. Photoinduced electron transfer generating the radical

• rule [43]. However, helicenes have not been broadly considered as potential photocatalysts or sensitizers or their applications were unsuccessful [44]. Recently, one of our groups exploited the highly reducing polyaza[7]helicene (Aza-H, see Scheme 1 for its structure) for sulfonylation/arylation three

• mechanism of the recently reported sulfonylation/arylation [45][46] reaction using laser flash photolysis (LFP). LFP is a powerful spectroscopic tool in photocatalysis that allows us not only to distinguish between energy and electron transfer but also to detect transient triplet states and radicals

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• modifying their physical properties, and stability and controlling the reactivity of arylation processes, as demonstrated in various studies [9][10]. For instance, the Gaunt group reported that the use of a fluoride counterion in diaryliodonium(III) salt can trigger phenol O-arylation by activating the

• -arylation using aryl(2,4,6-trimethoxyphenyl)iodonium(III) acetates [13]. In this process, the acetate ligand acted as a base to activate the phenol group and positioned it in proximity to accomplish the smooth SNAr reaction. The synthesis of diaryliodonium(III) salts with various counterions, such as

• triflate (TfO−) [14], tetrafluoroborate (BF4−) [15], tosylate (TsO−) [16], and others [17], has been extensively studied, as they play a key factor in the participation of iodonium salts in diverse arylation reactions. Recently, efficient syntheses of diaryliodonium(III) trifluoroacetates have been

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

• regioselective Ru-catalyzed direct carbonylative arylation of heterocycles developed by Beller et al. in 2014 [77]. In this paper various heterocycles were investigated including five examples of indoles. Another example was reported by Driver an co-workers, who developed the Pd-catalyzed direct aryl C–H

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• herein an enantioselective palladium-catalyzed Heck–Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation

• -pyrroles posed some challenges due to substrate instability and undesirable side reactions. In 2003, we reported the Heck–Matsuda arylation of N-protected 2,5-dihydro-1H-pyrroles [10] to obtain 4-aryl-γ-lactams in a racemic manner [11], thus demonstrating the feasibility of this transformation. The γ

• presence of a methoxy group after the Heck–Matsuda reaction indicates methanolysis after arylation. Given the importance of the lactam rings, we envisioned a sequential Jones oxidation protocol without isolation of the methyl N,O-acetal products to obtain the corresponding lactams 4. As observed in

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• 91 and 92 enabled the metallaphotoredox arylation (to 93) and alkylation (to 94) of the cubane core. Comparative physicochemical or biological data for the 1,2-cubanes was not reported. Isosteres of meta-substituted benzenes Many of the scaffolds previously discussed as potential bioisosteres for

• 1,4-BCHs (Scheme 11B) [55]. From carboxylic acid 100e, Curtius rearrangement led to amine 101 and a photoredox decarboxylative conjugate addition to diester 102. From boronate ester 100f, oxidative deborylation led to alcohol 103, arylation led to furan 104 and Matteson homologation to boronate ester

• methylation of the intermediate diacid. As for the 1,2-cubanes, the authors were able to derivatise this general building block into a range of other 1,3-cubanes via metallophotoredox catalysis using acid 167 and redox active esters 168 and 169 (Scheme 17B) [51]. Arylation (to 170), amination (to 171) and

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

• investigations demonstrated the ability of diaryliodonium salts for selective mono-arylation of 2-naphthols [34]. In this context, we embark on a strategy to modify the neighbouring position of the diaryliodonium salt with an ester group, presenting a novel copper-catalysed regioselective arylocyclization of

• for the synthesis of functional materials via cross-coupling reactions. Next, we extended our investigation to 1-naphthol in this reaction, and found that the arylation of 1-naphthol was achieved selectively at the C-2 position. The cascade cyclization resulted in the corresponding products 3an and

• 3au and 3av were produced in 34% and 39% yields, respectively, in which methoxy and tert-butyl groups were located in the para position to the hydroxy group (Table 2, entries 20 and 21). In the case of 3al, the mono-arylation of naphthol generated 3al’ in 20% isolated yield, which is the reason for