Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• hemiaminal opening and amine–ketone condensation, iminium ion 65 was produced for the next pyrrole nucleophilic addition to form a strategically important C–C bond and afford 66, which was protected as Boc carbamate in the same pot to give 67 in 96% yield from 64. In this tandem sequence, the nucleophilicity

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• substituents. Under the catalysis of IPrAuCl/AgSbF₆, substrates bearing unsubstituted terminal alkynes underwent 7-exo-dig cyclization driven by the strong nucleophilicity of the 3,5-dimethoxyphenyl group, exclusively affording dibenzo[b,d]azepine 54 (Scheme 12, path a). Conversely, substrates with aryl

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• (CN ≈ COR >> NO2) reacted poorly. Iodanes, containing electron-withdrawing groups with low nucleophilicity (CF3), however, gave fair yields. We also found that ortho-substituted iodanes did not provide arylation products, which can be attributed to the unfavorable steric hindrance [30]. Iodanes

• -butyldimethylsilyl)hex-5-yn-1-yl)-N-phenylaniline (15). Thus, acylamides were found to have optimal pKa and nucleophilicity to react according to our desired pathway (Scheme 4). For the heterocyclization mechanism under arylating conditions, we propose a Cu(I/III) catalyzed pathway (Scheme 5). Firstly, the copper(I

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• ]; this, despite an earlier demonstration of the superior nucleophilicity of BDC-NH2 [45]. Interestingly, this apparent reversal in reactivity was most significant with aliphatic isocyanates, while the reactivity reverted to what is expected with the use of more activated isocyanates. Subsequently, we

Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• in the formation of cyclohexane-1,2-dicarboxamides 4 due to their poor nucleophilicity. Finally, (1S,2S)-N1,N2-bis((1R,2R)-2-(sulfonamido)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamides 4 were cyclized with the Hendrickson reagent (triphenylphosphonium anhydride triflate in situ generated from

• cyclized product 5e in a low yield of 30% due to its poor nucleophilicity. However, 1,2-cyclohexane-1,2-dicarboxamide 4f with two very strong electron-poor trifluoromethyl groups did not undergo cyclization due to its very poor nucleophilicity. The results are collected in Table 1. Following the similar

• )-N1,N2-bis((1R,2R)-2-(tert-butoxycarbonyl)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide (4h) in 65% yield through the reaction with (1S,2S)-cyclohexane-1,2-dicarboxylic acid (3). However, compound 4h did not undergo cyclization possibly due to weak nucleophilicity and steric hindrance of the Boc

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• system, a variety of other factors commonly influences both the reaction rate and the stereochemical outcome of the glycosylation reaction, including the reactivity of the acceptor hydroxy group, the effect of remote protecting groups and a balance between the nucleophilicity of the acceptor and the

• glycosyl donor, the influence of remote protecting groups on donor reactivity and acceptor nucleophilicity should not be underestimated. This necessitates careful optimization of reaction conditions and the rational selection of compatible donor–acceptor pairs [77]. Protecting groups can also be used to

• its derivatives include the use of β-ᴅ-psicofuranosyl donors [84][85] and the intracellular aglycon delivery (IAD) strategy [86]. Electron-withdrawing groups, often used for the temporary protection of hydroxy functions in pyranoses, can significantly reduce the nucleophilicity of both glycosyl donors

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• 72% yield and excellent regio- and stereoselectivity. Regarding the acceptor, compound 6 harbored two free alcohol groups at the C3 and C2 positions. Since the C3 alcohol group is less sterically hindered and exhibits better nucleophilicity, the glycosidic bond formed regioselectively at the C3

• position. Additionally, THF was used as a solvent to enhance the α-selectivity of the reaction [41][42][43]. Next, while both compounds 8 and 9 can act as acceptors, compound 9, a primary alcohol, exhibits greater nucleophilicity. Using the TolSCl/AgOTf promoter system at −70 °C, the β-linked disaccharide

• 10 was formed, giving 71% yield (α/β = 1:6). According to the RRV/Aka platform [44], compound 9 is a robust nucleophile, with an Aka value of 12 [45]. This high nucleophilicity favors a SN2-like mechanism, promoting β-selectivity [46]. Using the difference in acceptor reactivity and activation method

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• publications [15], or/and from secondary processes, like an intramolecular rearrangement. Taking into account the postulated basicity (and nucleophilicity) of thiocarbonyl S-methanides 1 derived from cycloaliphatic thioketones [6], the initiating step of these processes can be presented as protonation of the

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

Optimized synthesis of aroyl-S,N-ketene acetals by omission of solubilizing alcohol cosolvents

• Julius Krenzer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2025, 21, 1201–1206, doi:10.3762/bjoc.21.97

• -condensation of 2-methylbenzothiazolium salts 7 and intermediary formed S,N-ketene acetals 4 at elevated temperatures. Einhorn acylation is governed by the electrophilicity of the acid chloride or acylammonium species and the nucleophilicity of any nucleophilic species present in the reaction mixture. In

• addition, since condensations are affected by the bimolecular addition as an elementary step, special attention to the concentration of the nucleophiles has to be paid. According to Mayr’s nucleophilicity scales [8][9][10], a nucleophilicity parameter N for the specific S,N-ketene acetal intermediate 4 can

• estimated from parameters for enamines (N = 10–16), cyclic N,N-ketene acetals (N = 18–20) [11][12] , and the deoxy-Breslow intermediate (N =15.6) [13]. The nucleophilicity of S,N-ketene acetal 4 clearly exceeds that of ethanol (N = 7.4). In addition, triethylamine is more nucleophilic (N = 17.30 in

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