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

• standard Cu-catalyzed electrochemical protocol. Based on mechanistic studies, the proposed mechanism is shown in Figure 9. First, hydroquinone 34 is oxidized at the anode to generate a quinone intermediate 38. Meanwhile, the chiral copper catalyst reacts with the Schiff base 33, generating a nucleophilic

• standard conditions. Subsequently, radical-polar coupling between electrophilic Ni-bound α-carbonyl radical intermediate 45 and remaining nucleophilic Cu-enolate 44 provides a chiral product 42 containing vicinal quaternary stereocenters with high stereoselectivity, and all three possible stereoisomers of

• an alkene to generate a radical intermediate, followed by oxidation, which enables radical-polar crossover (RPC) and the subsequent nucleophilic attack of the cationic intermediate [67]. Alternatively, the initial radical intermediate can be trapped by a transition-metal catalyst, followed by a cross

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• to multiple C–C bonds generates extended carbon radicals capable of giving further functionalization. Regarding the ionic mechanism, the key step generally comprises the complexation with the unsaturated substrate leading to activation of the alkenyl/alkynyl moiety towards a nucleophilic attack. In

• some cases, activation of a carbonyl group by the copper catalyst to facilitate nucleophilic attack has also been reported. Moreover, both activations can be operative simultaneously. Since copper shows affinity either for multiple C–C bonds or polar functional groups, it seems the ideal tool for this

• (Scheme 16) [33]. The reaction, which occurs with formation of C–C, C–N and C–O bonds, involves a nucleophilic addition of the activated alkyne XIV to the in situ-generated iminium ion XV, followed by cyclization to form a quinoxalin-2-one intermediate XVI. A subsequent 5-endo-dig cyclization involving

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• intermediate Int-9. As the assumed rate-determining step the intramolecular nucleophilic addition takes place, followed by further cyclization and finally, release of the organocatalyst to form the axially chiral product 9. Various aryl-substituted indolines 9 were obtained in good yields and high enantiomeric

• enantioselectivity during the nucleophilic addition, and the subsequent aromatization completes central-to-axial chirality conversion delivering products 68. Dynamic kinetic resolution of naphthylindoles 69 was performed by reaction with bulky electrophiles such as azodicarboxylates 70 or o-hydroxybenzyl alcohols 72

• . The proposed reaction pathway follows hydrogen bonding with alkynylnaphthylamine and later nucleophilic addition of the allene intermediate. The synthesis on the preparative scale provided product 183 with almost no deterioration in yield or enantioselectivity (90%, 91% ee). This product could then be

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

• , photoredox-catalytic, and nucleophilic aromatic substitution reactions, as well as in the two-step synthesis of cyclobutanone. The molecules synthesized under the optimal conditions are presented in Figure 6b, employing the stable noisy optimization by branch and fit (SNOBFIT) algorithm. SNOBFIT offers a

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• available 2-bromo-4-fluoro-1-nitrobenzene, featuring a noble-metal-free system, mild reaction conditions, and a good yield, especially for the final Cs2CO3-facilitated nucleophilic substitution (77–91% yield). The characterization data obtained from IR and NMR spectroscopy (1H, 13C, 19F, and 31P) as well as

• hand, we turned our attention to the synthesis of PhFlOP-based compounds through a Cs2CO3-facilitated nucleophilic substitution with substituted carbazoles as the nucleophiles (Scheme 2). For example, tert-butyl, bromo, carbazolyl, or phenyl substituents were introduced into the carbazoles. To our

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• in electrophilic transfer reactions, with emphasis on umpolung reactivity of usually nucleophilic functional groups. Thus constituting a powerful synthetic tool, opening room for new synthetic disconnections [10]. Within the benziodoxol(on)e class, a range of HIRs featuring nitrogen-containing groups

• reaction (Table 1, entry 1) [4]. In the presence of potassium carbonate, only starting material 4a was detected. A stronger base to generate the nucleophilic intermediate was tested, and sulfonamide 5aa was detected in trace amounts (Table 1, entry 2). Considering the low solubility of the hypervalent

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• chains and derived from the classical triphenylene core self-assembling in columnar mesophases based on this paradigm. These mesogenic compounds were simply obtained in good yields by the nucleophilic substitution (SNFAr) of various types of commercially available fluoroarenes with the electrophilic

• subsequent second annulation, yielding a new series of extended polyaromatic mesomorphic compounds, i.e., 1,1',3,3',4,4'-hexafluoro-6,6',7,7',10,10',11,11'-octaalkoxy-2,2'-bitriphenylene (Gnm) which were found to display a Colrec mesophase. The specific nucleophilic substitution patterns of the Fn

• red-shift of the emission peak. Keywords: arene–perfluoroarene interaction; decafluorobiphenyl; fluorinated triphenylene; fluoroarene nucleophilic substitution; organolithium; Introduction Non-covalent arene–fluoroarene intermolecular interactions [1][2] are drawing increasing attention due to their

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• hydrogen bonding with the protonated tertiary amine. Then, a Michael addition of malononitrile to the azadiene takes place to obtain exclusively the (S)-intermediate A. Subsequently an intramolecular nucleophilic addition of the nitrile leads to the intermediate B, which undergoes tautomerization to

• -derived azadiene by H-bonding. This dual activation promotes a stereoselective addition of 3-chlorooxindole to the azadiene leading to intermediate A. The latter is also activated by the chiral guanidine and undergoes an intramolecular nucleophilic substitution which delivers the product 19b with the

• the nitrogen atoms. Then, the azlactone enolate undergoes a nucleophilic attack on its Si-face via Mannich reaction with the 2-benzothiazolimine leading to intermediate A which evolves toward its resonance form B, responsible of the intramolecular attack of the negatively charged nitrogen to the

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• derivatives [1]. In particular, the catalytic isomerization of 5-chloroisoxazoles allows the generation of azirine-2-carbonyl chlorides, which can be easily converted into a variety of azirine-2-carboxylic acid derivatives by reactions with nucleophilic reagents. Using this approach, numerous 2-(1H-pyrazol-1

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

• fluoroalkyliodonium salts as sources of electrophilic trifluoroethyl synthon. Given the non-nucleophilic nature of the iodoarene byproduct, this protocol should not suffer from further reactivity that decomposes the ylide. We describe here the coupling of α-carbonyl sulfoxonium ylides with polyfluoroalkyl(aryl

• arene moieties. These observations confirmed the LUMO as an appropriate lobe for nucleophilic attack via the SN2 pathway (path 2), and confirmed the LUMO+1 as an appropriate lobe for substitution via reductive elimination (path 1). As such, neither mechanism could be immediately discarded, and we were

Controlled oligomerization of [1.1.1]propellane through radical polarity matching: selective synthesis of SF₅- and CF₃SF₄-containing [2]staffanes

• Jón Atiba Buldt,
• Wang-Yeuk Kong,
• Yannick Kraemer,
• Masiel M. Belsuzarri,
• Ansh Hiten Patel,
• James C. Fettinger,
• Dean J. Tantillo and
• Cody Ross Pitts

Beilstein J. Org. Chem. 2024, 20, 3134–3143, doi:10.3762/bjoc.20.259

• , e.g., a radical or cation) on the transannular carbon atom of a bicyclopentyl moiety can interact through space [35][63][64]. The consequence is ostensibly that more "nucleophilic" INT2 and INT5 are better matched for Cl atom abstraction from the "electrophilic" reagent (SF5Cl or CF3SF4Cl). To test

• becomes more negative (or less positive) the farther it is from either the SF5 or CF3SF4 substituent, consistent with the notion that it becomes more nucleophilic. Moreover, the Δq is largest between the first two intermediates in both series – INT1 vs INT2 and INT3 vs INT4 – indicating that the most

• [72][73][74]. The data show that BCP has a higher N value – thus stronger nucleophilic tendency – compared to both SF5Cl and CF3SF4Cl. Conversely, comparison of ω values shows significantly higher electrophilicity of SF5Cl and CF3SF4Cl compared to BCP. These results, coupled with decreasing ω and

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

• firstly through the coordination of an alkene by the HVI reagent, which activates it toward intramolecular attack by an internal nucleophile. Following this, substitution of the iodane(III) can occur from the nucleophilic halide in solution to reveal the halo-cyclised product (Figure 2). In this review

• fluoride ion to displace PhI. In pathway B (bottom), the nitrogen is oxidised by the iodane, generating an electrophilic intermediate B. Nucleophilic attack by the double bond subsequently forms the 6-membered ring intermediate C, which is either immediately attacked by fluoride to form both cis and trans

• ring A (Scheme 2). The Pd(II) intermediate is oxidised by PhI(OPiv)2/AgF, forming Pd(IV). Formation of the product can occur either by reductive elimination by Pd(IV) or SN2 nucleophilic attack by fluorine with concomitant palladium reduction. Reductive elimination of the Pd(II) intermediate forms the

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

• (Table 5). DFT calculations predicted that the catalytically active species is the adduct of porphyrin and TBACl (18-I), which forms an activated complex (18-II) with the substrate followed by a ring-opening nucleophilic attack of Cl−. The electron-rich nitrogen atom in 18-III further activates

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• thioesterase (TE) domain and determines the topology of the final NRP product. The TE may release the NRP as a linear peptide or cyclic peptide, and the latter further manifests many possible topologies (Figure 5b). In a nutshell, offloading is a TE-catalyzed nucleophilic attack to release an NRP from the

• offloading step always entails the same chemical reaction, wherein nucleophilic attack is promoted by the catalytic triad of a TE via general base catalysis. This is likely why traditional mechanistic studies that focused on the enzyme active site failed to work out how TEs control NRP topology. A priori

• , respectively. Based on the position of the nucleophile, a NRP can be cyclized head-to-tail, via an amino acid side-chain, a nucleophilic heteroatom on the N-terminal fatty acyl chain, or as a multimer of repeating sub-structures (Figure 5b). The ring size, ratio of ʟ- and ᴅ-amino acids, etc. may also be the

Cyclodextrin-based rotaxanes for polymer materials: challenge on simultaneous realization of inexpensive production and defined structures

• Yosuke Akae

Beilstein J. Org. Chem. 2024, 20, 3026–3049, doi:10.3762/bjoc.20.252

• structure in the early days. Rotaxane bearing a dumbbell comprising only covalent bonds was first reported by Harada and co-workers in 1997 (Scheme 1B) [38]. In this system, the end-capping reaction was based on the nucleophilic substitution of the amino groups on the axle ends. Afterward, such nucleophilic

• synthesis, Harada and co-workers reported the end-capping reaction based on nucleophilic substitution by the amino groups on axle ends (Scheme 2) [43]. Similarly, other highly efficient reactions have been performed as end-capping reactions to produce polyrotaxane [13][14][15]. In addition to the simple

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

• mainly include: nucleophilic addition or nucleophilic substitution with H2O2 or ROOH [17][18], autoxidation with O2, pericyclic reactions of unsaturated bonds with O3 or O2, and metal-catalyzed peroxidation (Isayama–Mukaiyama hydrosilylperoxidation [19][20], for example) [21][22][23]. As the topic is

• generate the nucleophilic carbon radical B. The intramolecular 1,5-HAT of B provided the alkyl radical C, which then cross-coupled with the in situ-generated high-valent Mnn+1OO-t-Bu species to form the 1,6-difunctionalized product 42 via peroxy-ligand transfer. The remote trifluoromethylthiolation

• be generated by nucleophilic attack of the tert-butylperoxy radical to the radical intermediate A or TBHP to the carbocation intermediate B. Using carboxylic acids 215 and TBHP, the synthesis of β-peroxy-α-acyloxy derivatives 216 was developed via the TBAI-promoted acyloxylation–peroxidation of

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• 20 in a yield of 89% [13]. To convert the iodo to an OH group, compound 20 was reacted with Cu2O, 2-pyridinaldoxime and CsOH to give 2-hydroxy-3,4,5-trimethoxybenzaldehyde (21, 65%) [13]. In a subsequent nucleophilic substitution, the fluorinated alkyl chains of 16, 17, and 18 were linked via a

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• synthesis, e.g., via pericyclic reactions or nucleophilic additions. Results and Discussion We commenced our research by screening the nature of the base to generate carbanion at alpha position. We chose 2,3,3,3-tetrafluoro-N-heptylpropanamide, obtained according to the procedure developed earlier in our

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

• compounds (Scheme 16) [68]. The novel iodine(III) intermediate was generated through nucleophilic substitution of a heteroatom nucleophile, which initiated the reaction. A subsequent aryl migration from the iodine to the heteroatom resulted in the formation of the arylated nucleophile. In addition to

• diaryliodonium salts 40 (Scheme 18) [69], which however, does not produce the diarylated compounds. The intramolecular aryl migration from the iodine to the nitrogen leads to a quaternary ammonium ion intermediate A. Consequently, a nucleophilic ring opening of cyclic amine in 42 occurred via cleavage of the

• intramolecular. In the presence of a base, the triflate anion is extracted, forming a cationic trifluoromethanesulfonyl group as an intermediate. Thus, the products are believed to form via a sulfonyl-directed nucleophilic aromatic substitution pathway. Finally, the products are obtained through the dissociation

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

• of 5-thioxo-1,2,4-triazolium inner salts by the nucleophilic thiocyanation of N,N-dialkylhydrazonoyl bromides, in situ generated from aldehyde-derived hydrazones in the presence of an oxidant (NBS, (NH4)2S2O8), Scheme 1). In 2024, the synthesis of 2‑imino-1,3,4-thiadiazoles was achieved by

• % yield) using readily available reagents, namely NBS and the nucleophilic reagent AgSCF3. This approach provides a straightforward access to an unprecedented class of trifluoromethylthiolated derivatives. This method offers new avenues for synthesizing a plethora of valuable SCF3-containing molecules

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• addition to the application of isocyanides in a variety of MCRs, one of the unique reactions involves the formation of zwitterions from isocyanides upon reaction with acetylene and active olefin compounds such as alkyl acetylenedicarboxylates and gem-diactivated olefins. Due to having nucleophilic and

• electron-donating substituents (Scheme 3). The cause of this phenomenon is probably related to the electron-widthdawing effect of these substitution groups in olefin, which affects the nucleophilic attack of the isocyanides. When a carboxylate substituent was present instead of the carbonitrile in the gem

• synthesizing pyrrole-fused dibenzoxazepine is illustrated in Scheme 5. The reaction is initiated by the nucleophilic attack of the isocyanide 2 on the gem-diactivated olefin 1 to give the zwitterion intermediate 7. The reaction proceeds with the nucleophilic attack of the zwitterion intermediate 8 on the

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• reagents is rather limited. Indeed, most examples involve dimethyl- or diethylzinc compounds as more elaborated dialkylzinc reagents represent a considerable synthetic challenge. Indeed, dialkylzinc reagents are accessible essentially through nucleophilic displacement of ZnCl2 by Grignard reagents or

• remains tenuous. Indeed, until recently, mixed alkylzinc species were only employed by Carretero and co-workers in related nucleophilic additions to activated imines under Cu catalysis [22]. In 2022, our group demonstrated that alkyl iodides offer a reliable source of heteroleptic organozinc compounds

• nucleophilic organozincate complexes (e.g., LiBuZnBrCl), which is a well-established process in THF [29][30]. Due to the hygroscopic character of LiCl and the necessity to determine the amount of organozinc by iodolysis [20] in order to adjust the stoichiometry of the reagents for the multicomponent coupling

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• -acylamine; oxazole; propargylamine; Introduction Propargylamine is an important motif in the synthesis of heterocyclic compounds [1][2][3][4] and drug discovery [5][6] due to its multifunctionality, which includes a basic and nucleophilic amino group, an electrophilic and dipolarophilic triple bond, and an

• ] because of their easily modifiable dipeptide frameworks. Several methods exist for accessing PCPAs, such as the amination of 1-halo-1-alkynes [16][17], tandem reactions of α-imino esters with nucleophiles and electrophiles [18], and the nucleophilic addition of an acetylide to α-carbonylated N-acylimines

• derivative has been employed (Scheme 1) [13][14]. Recently, we have demonstrated that the central carbonyl group of DEMO is highly electrophilic, facilitating the nucleophilic addition of less reactive reagents such as acid amides [23][24][25][26]. When the reaction was conducted in the presence of acetic

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• polyfunctional precursors 1, 2, and 3, two pathways are theoretically possible (Scheme 2 and Scheme 3). The first one involves the N-nucleophilic Michael addition to the activated multiple bond of the imide, leading to the formation of linear intermediates 6 or 8 (pathways A1 and B1) at the expense of the endo

• imidazole nucleophilic center not involved in the first step. This process leads to the formation of alternative final products: imidazo[1,2-a]imidazoles 10 and 12, imidazo[1,5-a]pyrimidines 4, 5, 11 and 14, and imidazo[1,2-a]diazines 13 and 15. The analysis of the spectral data (1H and 13C NMR, 2D NMR

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• by these findings, we now explored difluoromethylation reactions with compounds bearing less nucleophilic functional groups. Ketones caught our particular attention as they contain a weak nucleophilic carbonyl oxygen adjacent to an electrophilic carbonyl carbon. Previous studies have focused on

• with the generation of difluorocarbene from TMSCF2Br and KFHF. This is followed by a nucleophilic attack of the oxygen atom of ketone 1 on the difluorocarbene. Subsequently, a protonation–deprotonation sequence occurs, which can either be intermolecular, involving a molecule of HF, or intramolecular