Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• reacts with the enolate of the ketone, which is stabilized by coordination with Fe(III), resulting in the formation of the C–C bond. A further oxidative aromatization process affords compound I. Compared to the protocol developed by Zhang et al. [24], the reaction is less regioselective, as Troger’s base

• which, after MMS formation, this reactive species is subsequently captured by the stabilized Cu(II) enolate of the ketone, to provide an α,β-unsaturated ketone intermediate F. This compound condenses with the aniline component to give an imine G that follows a cyclization and aromatization cascade

Synthesis of the aggregation pheromone of Tribolium castaneum

• Biyu An,
• Xueyang Wang,
• Ao Jiao,
• Qinghua Bian and
• Jiangchun Zhong

Beilstein J. Org. Chem. 2025, 21, 510–514, doi:10.3762/bjoc.21.38

• enolate of diethyl malonate yielded (S)-2-(hex-5-en-2-yl)malonate ((S)-6), and realized a stereospecific inversion of chiral secondary tosylate (R)-5 [30][31]. The geminal ester (S)-6 was next treated with NaOH in methanol to afford (S)-2-(hex-5-en-2-yl)malonic acid ((S)-7) in 96% yield [32]. Then

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

• identical racemic carbonyl nucleophiles to generate Cu-enolate 44 and Ni-enolate 43 simultaneously (Figure 10). The Ni-enolate 43 undergoes anodic oxidation through single-electron transfer, releasing nickel-bound α-carbonyl radical 45, whereas the copper complex 44 remains electrochemically inert under

• 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

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

• transformation relies on the catalysis with azolium precatalyst C12 (Scheme 11a). The reaction also allowed the synthesis of indol-derived bridged biaryls 35 (Scheme 11b). The proposed mechanism, supported by DFT calculations, comprises propargylic substitution towards Int-20 with NHC-derived enolate Int-19

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

• their structure will be described. In 2012, Wang and co-workers reported a bifunctional thiourea-catalyzed aza-Diels–Alder reaction of cyclic keto/enolate salts 1 and N-tosyl-2-methylene-but-3-enoates 2 (Scheme 1). After a screening of the reaction conditions they found that organocatalyst I, acetic

• the α-position led to the desired products albeit with unsatisfactory results. The bifunctional squaramide catalyst V has two functions; firstly it deprotonates the enolic form of the azlactone through the Brønsted-base moiety, and secondly it activates the 1-azadiene and enolate form of the

• azlactones through H-bond interactions with the squaramide moiety. The activated complex undergoes a [4 + 2] cyclization, through the Si-face attack of the enolate to the 1-azadiene leading to intermediate A which undergoes tautomerization and protonation to yield the chiral tricyclic derivative 16. To

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

• . Next, TiCl4 as metal enolate mediator was applied. In the presence of both, Et3N as well as N,N,N′,N′-tetramethyl-1,3-propanediamine no reaction was observed (Table 1, entries 3–6) [40]. With titanium chloride and n-BuLi, low conversion of the starting material and obtained product Z-9a was

Structure and thermal stability of phosphorus-iodonium ylids

• Andrew Greener,
• Stephen P. Argent,
• Coby J. Clarke and
• Miriam L. O’Duill

Beilstein J. Org. Chem. 2024, 20, 2931–2939, doi:10.3762/bjoc.20.245

• -centre-4-electron bond is slightly distorted from linear geometry by 5–20° (Table 1). The short C–P and C–C bonds (d and e) in the phosphorus ylid moiety confirm Moriarty and Zhdankin’s observation that the ylid exists mainly in its enolate form (Figure 1B) [24][25] to stabilise the build-up of negative

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

• upon binding of the enolate molecule to iodine either through a carbon–iodine or an oxygen–iodine bond. Both intermediates, I and II, are in rapid equilibrium with each other and further undergo two different types of reactions: [1,2]-ligand coupling and [2,3]-rearrangement (Scheme 2). Either of these

• base-mediated deprotonation of substrates 86 produces the corresponding ester enolate. This enolate undergoes a retro-Michael reaction, generating sulfenate anion A. The sulfenate anion A then nucleophilically attacks the diaryliodonium salts 16, forming hypervalent iodine intermediates B. Finally

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

• reactions of difluorocarbene with cyclic and acyclic 1,3-diones (Scheme 1A) [41][42][43][44][45]. Typically, they were conducted with a base to form the corresponding enolate anions which then reacted with difluorocarbene to yield difluoromethyl enol ethers. Those products are of interest because they

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

• chelation interaction between the enolate derived from acyclic 1,3-dicarbonyl compounds and copper (Scheme 5, 8a–j). Detailed control experiments indicate that the terminal alkyne moiety is critical and the reaction proceeds through an SN1 mechanism. An outer-sphere nucleophilic attack through copper

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

• mechanism starts with the formation of a nickel-chelated enolate intermediate, followed by the anodic oxidation to form the nickel-coordinated carbon-centered radical intermediate. Another mechanism is proposed for alkyl-substituted acylimidazoles. In this case, the additive ferrocene (Cp2Fe) serves as

• mediator between the anode and the nickel-chelated enolate intermediate. Simultaneously, the amine substrate is oxidized at the anode and deprotonated to generate a nitrogen-centered radical. The desired product then is generated by the stereoselective cross-coupling of the carbon-centered radical with the

• orbital during enolate formation, thus providing mild redox conditions. After anodic oxidation, a carbon-centered radical at the α-position is formed, which undergoes stereocontrolled C–C-bond formation with the silyl ether, forming a trimethylsilyl (TMS)-ketyl radical. A second anodic one-electron

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

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

• oxalate (9) and alkylphenones 10 through a sterically hindered Claisen condensation, producing a six-membered lithium enolate salt. Subsequent cyclocondensation with hydrazines concludes the formation of pyrazoles. However, this process could not be performed as a one-pot synthesis, as the solvent had to

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• double Michael adduct 3n in 56% yield (Table 2, entry 14). A plausible mechanism for the cascade double and triple Michael reactions is shown in Scheme 2. At first, the enolate I of curcumin 1 adds to arylidenemalonate 2 in a Michael fashion resulting enolate II. The ester enolate II might remain in

• equilibrium with 1,3-dicarbonyl enolate I, but the former would be trapped via cyclization involving a diastereoselective 6-endo-trig intramolecular Michael addition to the enone moiety leading to highly substituted cyclohexanone 3. The formation of triple Michael adduct 4 can be attributed to the enolate 3

• curcumins 1 with arylidenemalonate 2 can be explained in terms of the relative stereochemistry of the substituents in the enolate arising from the first Michael addition (Figure 3). Comparison of the two possible transition states TSI and TSII for second Michael addition suggests that a severe 1,3-allylic

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

• , presumably due to entropic penalties. Three of four computed resonance forms were all found to be of approximately equal energy. Only the E-enolate form 6 (-N1H-E) was slightly higher in energy by 0.06 kcal/mol likely due to electrostatic destabilization of the oxyanion with N2, however, this difference is

• molecules. Tautomerism of indazole. DFT-calculated deprotonation of 6 with Cs2CO3 in implicit THF with the temperature of the calculation set to 90 °C to simulate the dioxane conditions (top) and energy differences of four enolate resonance structures of 6 calculated as discrete structures. The hybrid is

• identified as 6(N-H) (bottom). DFT-calculated Cs+-coordinated complexes with different enolate forms of 6(N-H) calculated as isolated compounds (top) and calculated intermediates of the reactions of 6(-N1H-Z) and 6(-N1H-E) with Cs+ (bottom). DFT-calculated reaction coordinate diagram for the reaction of 6

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• reactions seem to take place through conjugated additions on the enol tautomer of the Ugi adduct. Indeed, the enolate intermediate would explain the stereochemical results, controlled by the configuration in the hemiaminal intermediate and not by the chiral information on the amine, unlike in the case of

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• the starting materials (nucleophilic approach), or rely on more advanced N3-transfer agents (electrophilic approach), over the course of the last years also α-azidations of enolate-type precursors using nucleophilic azide sources under oxidative conditions have been introduced very successfully [24

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• allenoates 3 delivering highly functionalized α,α-disubstituted α-amino acid derivatives 5 has so far not been systematically addressed (for recent other β-selective additions of enolate precursors to allenoates please see references [31][32][33][34]). Thus, we now became interested in testing this

(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

• ]propellane (129). Gassman reported the initial synthesis of [3.1.1]propellane (129) in 1980 [61], and this was recently optimised by Uchiyama (Scheme 13A) [47]. Cyclisation to the bridged structure 126 was achieved by enolate formation and intramolecular nucleophilic substitution of iodide diester 125. A

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• reactive enolate 1a-enolate. Nitrogen-centered bases react with fluorine gas to form N-fluoroammonium fluorides and fluoride ion [49]. Thus, on addition of tertiary amines, fluorine can react to generate basic fluoride ions and deliver reactive, electrophilic N–F species. Given that Selectfluor is

• anionic 1a–i-enolate species in parallel with N-fluoroammonium ion 6. Fluoride ions formed through the reactions between fluorine and quinuclidine or fluorine and enolate species, may deprotonate 1a–i-enol, to form enolates of 1a–i that are reactive towards both fluorine and N-fluoroammonium ion 6. The

• effective base to facilitate the formation of 1a-enolate from 1a-enol and thus facilitate the initial monofluorination step by either fluorine or N-fluoroammonium ion 6. Carbonate ions are also expected to be highly basic in MeCN, however, their limited solubility is likely to inhibit their ability to act

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• (Scheme 30B). Then, cesium carbonate deprotonates the enol OH in 145, to provide the enolate form of Breslow’s intermediate 146, which is a suitable reducing agent to trigger the fragmentation of NHPI ester 58 (E°ox = −0.97 V vs SCE in MeCN). Hence, it is proposed that enolate 146 induces the single

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• facile stereoselective tandem reaction based on the asymmetric conjugate addition of dialkylzinc reagents to unsaturated acylimidazoles, followed by trapping of the intermediate zinc enolate with carbocations [12]. A practical one-pot synthesis of fluorescent pyrazolo[3,4-b]pyridin-6-ones by reacting 5

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• regarded as stable phosphonium enolate zwitterions. The first zwitterions of this type were published in 1955 [31], but the first crystal structure of a phosphonium enolate zwitterion was reported only in 2007 by Zhu et al., who synthesized the compound via a three-component coupling between an

• between the anionic phenolate and the cationic phosphonium center [32]. Other stable phosphonium enolate or phenolate zwitterions feature P–O distances in the range of 2.60–2.95 Å [28][32]. For comparison, in 1,2-oxaphosphetanes, the covalent bond between P–O is characterized by a distinctly shorter

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• introduced in 2017, followed by carbon nanotubes in 2019. Consistent with expectations from theory, anion–π catalysis on carbon allotropes generally increases with polarizability. Realized examples reach from enolate addition chemistry to asymmetric Diels–Alder reactions and autocatalytic ether cyclizations

• catalysis; electromicrofluidics; enolate addition; ether cyclizations; fullerenes; Introduction Anion–π catalysis was introduced ten years ago [1]. The idea is to stabilize anionic transition states on electron-deficient, π-acidic aromatic surfaces (Figure 1A). The true beginning is arguably in 2015

• because it took some time to find the benchmark reaction needed to develop the catalysts (Figure 2) [2]. With this operational enolate chemistry in hand, it quickly became clear that increasing π acidity at the same time decreases the stability of the catalyst [3][4][5]. This suggested that induced rather

Synthesis and biological evaluation of Argemone mexicana-inspired antimicrobials

• Jessica Villegas,
• Bryce C. Ball,
• Katelyn M. Shouse,
• Caleb W. VanArragon,
• Ashley N. Wasserman,
• Hannah E. Bhakta,
• Allen G. Oliver,
• Danielle A. Orozco-Nunnelly and
• Jeffrey M. Pruet

Beilstein J. Org. Chem. 2023, 19, 1511–1524, doi:10.3762/bjoc.19.108

• considered ways to further enhance this activity. We first explored the effects of structural modifications to berberine itself. The cationic iminium within berberine and its derivatives is susceptible to nucleophilic attack [10][14]. Through use of an acetone enolate, as well as partial or full reduction by