A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• electronic imbalance reduces the diene's nucleophilicity, rendering it less reactive to the dienophile. The unfeasibility of the IMDA reaction in this system arises from inadequate interatomic distances, electrostatic repulsion from incompatible associated dienophile was conducted [19][20]. Firstly, the

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• cinnamic acid (7) and N,N’-dimethylformamide (DMF)-mediated by POCl3 via acid chloride 36 formation (Scheme 20) [52]. On top of the carboxyl activation approaches demonstrated above, O/N-acylation could also be achieved by employing an electrophilic alkylating agent by exploiting the nucleophilicity of the

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• synthesis of spirocyclic compounds [1][2][3]. The nucleophilicity of isatin at the nitrogen atom allows it to participate in reactions such as alkylation [4], arylation [5], and aza-Michael addition [6][7][8]. However, the products obtained from these reactions are primarily achiral or racemic, and only a

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• first report by Stork in the 1950s [1][2][3]. Compared with enols, enamines benefit from the lone pair of electrons on the nitrogen atom, which enhances the nucleophilicity of the alkene, enabling it to react with a broad range of electrophiles. This activation mode of carbonyl compounds has been so

• enamides contain an N-acyl group in place of the original alkyl group. The electron-withdrawing effect of the amide group delocalizes the nitrogen lone pair, thereby reducing the electron density and nucleophilicity of the enamide double bond. These features significantly diminish the reactivity of

• , the terminal alkene remains intact during this process, and the initial protonation proceeds with full stereocontrol, rendering this transformation both highly chemo- and diastereoselective. From the cyclization result, it is presumed that the higher nucleophilicity of the alkyne functionality over

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• position of the pyrazole ring lacks sufficient nucleophilicity. To further expand the scope of our chemistry, we conducted a series of reductive post-assembly modifications of the pyrazolo[1,5-a][1,4]diazepine core, following our recently developed strategy for enriching the sp3 character in post-Ugi

Substituent effects in N-acetylated phenylazopyrazole photoswitches

• Radek Tovtik,
• Dennis Marzin,
• Pia Weigel,
• Stefano Crespi and
• Nadja A. Simeth

Beilstein J. Org. Chem. 2025, 21, 830–838, doi:10.3762/bjoc.21.66

• reactivity of the diazonium salt. When strong electron-withdrawing groups (EWGs) were introduced, the yield was also reduced, likely due to the low nucleophilicity of the aniline derivative and the ineffective formation of a diazonium salt. An annulation reaction of compound 2 was performed with either

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• addition, even though there was an excess of water as compared to methylamine in the reaction mixture, the nucleophilicity of water molecules is lower than that of the aliphatic amine [22]. Hence, the transimination reaction [23] has occurred reversibly in which the imine (C=N) linkage-containing resonance

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• cyanides versus isocyanides had been subject of high-level quantum chemical computations [54], and has gained interest lately [56][57][58]. Thanks to preferred isocyanide (rather than cyanide) coordination to calcium, the carbon atom in 9 has increased nucleophilicity, compared to that in 7 – an important

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• ). Apparently, for the realization of the presented condensation, the nucleophilicity of the aromatic amines is not sufficient. Wherein, the type of substituent in the aroyl fragment of furanone 1 doesn’t influence the result of this reaction. Thus, enamines 4 can be synthesized only using active aliphatic

• unsubstituted hydrazine. So, reflux of furanone 1a with hydrazine monohydrochloride in EtOH for 8 h resulted in a complex mixture of products (Scheme 5a). Taking into account the fact that the nucleophilicity of hydrazine is higher than for arylhydrazines and similar to alkylamines we tested the conditions

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• the regioselective glycosylation produced products 24:25 in a 4:1 ratio in 61% yield. Aglycon transfer was also observed in the reaction producing 26 in 15% yield. The predominance of product 24 also indicates towards a higher nucleophilicity of the C-4 position of the glucoside acceptor 26

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

• electrophilic amination reaction afforded sulfonamides 5aa, 5ba, 5da, and 5ea with moderate yields. However, no amination product was detected with tert-butyl 3-(benzylsulfinyl)propanoate (4c). This result suggests that aliphatic β-sulfinyl esters may not possess sufficient nucleophilicity to react with the

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

• dramatic change in bicyclopentyl radical philicity would arise after incorporation of the second BCP unit. In addition to charge models, we evaluated global reactivity indices (ω: electrophilicity index [70] and N: nucleophilicity index [71]) within the conceptual density functional theory (CDFT) framework

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 level of this chemoselectivity was dependent on the iodane ligand: OPiv was more selective for aminofluorination than OAc, which was proposed to be due to differences in basicity and nucleophilicity (Scheme 10). Detailed mechanistic studies were carried out using multinuclear NMR spectroscopy

• and N-bromosuccinimide (NBS), which promoted the intramolecular bromolactonisation of unsaturated acids 68. The authors investigated the oxidation using a variety of ortho-substituted iodobenzenes. Increasing the nucleophilicity of the groups at the ortho-substituted positions of iodobenzene gave

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

• nature of X− [45][46]. Anions like tetrafluoroborate, hexafluorophosphate, and trifluoromethanesulfate are commonly used in DAIS due to their good solubility and weak nucleophilicity. If the two aryl groups (Ar1 and Ar2) in DAIS are different, they are termed unsymmetric diaryliodonium salts 3. The

• factors like steric hindrance. The ring opening proceeded smoothly when nucleophiles with higher nucleophilicity are used yielding up to 99% of the desired products 43. The N-arylation of amino acid esters 44 was established with the utility of substituted phenyl(anisyl)iodonium triflate salts 45 (Scheme

• therapeutics, particularly in antibody–drug conjugates (ADCs). Cysteine (Cys) holds a special place in this context due to the distinctive nucleophilicity of its thiol side chain. The cysteine thiol group offers a reactive handle for site-selective modifications, allowing for the attachment of various

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• . These limitations suggest that a more viable approach to employing FLPs as catalysts for CO2-related reactions could involve their use in CO2 activation [7][18][19]. In particular, the capture of CO2 by FLPs enhances the electrophilicity of the CO2 carbon atom and the nucleophilicity of one of the CO2

Anion-dependent ion-pairing assemblies of triazatriangulenium cation that interferes with stacking structures

• Yohei Haketa,
• Takuma Matsuda and
• Hiromitsu Maeda

Beilstein J. Org. Chem. 2024, 20, 2567–2576, doi:10.3762/bjoc.20.215

• closure with aniline requires a base as reported by Laursen et al. [26], whereas 2,6-dimethylaniline in this study was reacted without the use of a base. This can be explained by the high nucleophilicity of 2,6-dimethylaniline, though it is sterically hindered. As counteranions affect ion-pairing

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• , Via Gobetti 85, 40129 Bologna, Italy 10.3762/bjoc.20.210 Abstract The direct nucleophilic addition of amides to unfunctionalized alkenes via photoredox catalysis represents a facile approach towards functionalized alkylamides. Unfortunately, the scarce nucleophilicity of amides and competitive side

• •] = +2.09 V vs SCE) [55][56]. The *PC+ species can oxidize the unsaturated lactam, thereby producing the corresponding radical cation intermediate A. The low stabilization by amide-bond resonance of the cyclic four-membered β-lactam [57][58] ensures a good nucleophilicity of the nitrogen atom to efficiently

Efficient one-step synthesis of diarylacetic acids by electrochemical direct carboxylation of diarylmethanol compounds in DMSO

• Hisanori Senboku and
• Mizuki Hayama

Beilstein J. Org. Chem. 2024, 20, 2392–2400, doi:10.3762/bjoc.20.203

• proton abstraction from DMSO to produce 3 as main product. It was thought that the increase of steric hindrance caused a reduction in nucleophilicity and an increase in basicity in the generated triphenylmethyl anion species, in comparison to the diphenylmethyl anion species. To elucidate the mechanism

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

• have also been used to predict the Mayr–Patz nucleophilicity parameter N, which estimates the nucleophilicity of a nucleophile based on experimentally measured kinetic data. The MLR models are used to predict N for more than 1200 nucleophiles, enabling the prediction of N for further nucleophiles [98

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

• amines with different nucleophilicity, namely benzylamine (primary alkylamine), morpholine (secondary alkylamine) and aniline (aromatic amine). We first examined the reaction of 1,2,4-oxadiazole-1,3-diketone 1a (σm/σp 0.463/0.575, which is quite close to the constants of the CO2Me group, so a successful

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

• base in the Knoevenagel reaction and as a component for ring formation. Cyclization is completely regioselective when arylhydrazines are used; with methylhydrazine, the ratio is greater than 10:1. In addition to malononitrile, derivatives with reduced nucleophilicity (X = CO2R) are also tolerated in

• chlorides furnishes alkynones 104 under mild reaction conditions [124][125]. Without isolation alkynones 104, hydrazines react directly by Michael addition–cyclocondensation, affording 1,3,5-trisubstituted pyrazoles 102 and 103 with remarkable regioselectivity (Scheme 37) [126][127]. The nucleophilicity of

• stabilization of the secondary nitrogen atom attenuates the nucleophilicity on the secondary nitrogen, furnishing regioisomeric product 103. This latter inverse regioselectivity is typical for arylhydrazines, and due to a lower overall nucleophilicity, often forcing conditions for the cyclocondensation are

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

• , Parr and Yang developed a now widely used index of nucleophilicity from robust electron population methods such as NBO analyses, referred to as the Fukui index (f-) [44]. The larger the Fukui index, the greater the nucleophilicity, and is thus inversely proportional to the partial charge. Our

• stabilization, nucleophilicity would dictate regioselectivity outcomes. This also implies that the favorable NCIs and chelation are stronger driving forces towards transition-state energy partitioning than nucleophilicity alone. These results suggest chelation is a highly plausible driving force for

• support the claim made by Alam and Keeting that a tight ion pair drives N1-selectivity when electron-withdrawing groups that can coordinate the cation are present at the 3-position. When 3-cyanoindazole is employed and no bidentate coordination is possible with N2, the nucleophilicity of N1 drives the

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

• its nucleophilicity and improving its orientation. Furthermore, Ser105 formed a strong hydrogen bond also with benzaldehyde, making it a better electron acceptor. Interestingly, also the imine intermediate showed strong interaction with Thr40 and Ser105 residues, so becoming a good electrophile for

• nucleophilicity. In their second work about this topic, Prasad et al. synthesized 5-(3”-alkyl/arylamino-1”-azaindolizin-2”-yl)-2’-deoxyuridines 31 as new base-modified fluorescent nucleosides with high Stokes’ shift, potentially useful for investigating nucleic acid structure and functions. The authors

• their reduced nucleophilicity. Also the synthesis of a bis-imidazo[1,2-a]pyridine scaffold was achieved in 43% yield from the pseudo-para-substituted bis-aldehyde, using the same conditions, but longer reactions times (6 days). Following the same approach, the authors also developed a one-pot protocol

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

• solubility issues of metal fluoride salts, safety issues with hydrogen fluoride, poor nucleophilicity [79], and side reactivity as a base [75][79], a few elegant examples of nucleophilic benzylic C(sp3)–H fluorination have been reported. Metal catalysis Fluoride sources have been used in combination with

• the ionic liquid 1-ethyl-3-methylimidazolium trifluoromethanesulfonate ([emim][OTf]) for the fluorination of phthalides at the benzylic position (Figure 37) [95]. It was considered that the zwitterionic nature of the ionic liquid served two purposes. Firstly, to enhance the nucleophilicity of fluoride

• dissolve caesium fluorides and facilitate an electrochemical benzylic C(sp3)–H fluorination of triphenylmethane (Figure 39) [97]. The authors suggested that PEG complexed the metal ion, increasing the nucleophilicity of the fluoride ion. Product 23 was achieved in 85% isolated yield after a small

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• -covalent catalysis via bifunctional hydrogen-bonding organocatalysts. The C-4 nucleophilicity of pyrazolin-5-ones was also explored in enantioselective reactions with α,β-unsaturated carbonyl compounds through covalent catalysis with chiral amine-based catalysts; however, it has achieved limited success