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

• ) annulation of enals with ynamides 8 to afford axially chiral 7-arylindolines 9 was reported [20]. The reaction mechanism, rationalized by DFT calculations, is believed to occur through catalyst C3 activation of the substrate 8, dehydration, and deprotonation with tautomerization leading to the enamine

• -Breslow-type intermediates with the chiral NHC-catalyst and subsequent deprotonation toward the nitrile product. Zhang, Wang, Ye, and co-workers utilized NHC-catalysis for the atroposelective synthesis of axially chiral diaryl ethers 59 and 61 [38]. This transformation was realized via desymmetrization of

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

• the squaramide moiety and a nucleophile through deprotonation as Brønsted base. On the other hand, a chiral phosphoric acid provides a confined chiral environment where the reactants are approached, activating both the azadiene by interaction with the acidic hydrogen and a dienophile bearing a

• catalysts are synthesized by joining together two fragments of cinchona alkaloids. In this manner, it is possible to obtain a symmetric catalyst, which can engage in hydrogen bonding interactions and deprotonation processes. Although they were originally used for Sharpless dihydroxylation, they have been

• patterns and aryl R2 substituents led to the desired products. However, the presence of a cyclopropyl or isopropyl R2 substituent, led to a complex mixture of products (Scheme 15). In the mechanism proposed by the authors, (DHQ)2PHAL XIII provokes the deprotonation of the γ-nitro ketone at the α-position

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

• deprotonation would complete the pathway. The alternative mechanistic proposal is an SN2 reaction [40][41][42] between 1a and the iodonium ion 2a’, which directly furnishes B without invoking halogen bonded adducts. To assess which of these mechanistic possibilities was more probable, we turned to computational

Surprising acidity for the methylene of 1,3-indenocorannulenes?

• Shi Liu,
• Märt Lõkov,
• Sofja Tshepelevitsh,
• Ivo Leito,
• Kim K. Baldridge and
• Jay S. Siegel

Beilstein J. Org. Chem. 2024, 20, 3144–3150, doi:10.3762/bjoc.20.260

• 32.2 [4], respectively (Scheme 1) [5][6]. The reaction enthalpy for deprotonation of CpH is ca 20 kcal/mol less endothermic than DPMH and ca. 24–27 kcal/mol less endothermic than 1,4-pentadiene (PDH; pKa ≈ 35 in DMSO) [3], values strikingly similar to the resonance stabilization energy estimated for

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

• [48]. Therefore, most of the work involving metal-free porphyrins is limited to investigations on N–H tautomerization and protonation–deprotonation studies [49][50][51][52]. However, there are several chemical tools to convert the planar geometry of porphyrins to nonplanar, such as functionalization

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

• -AcrClO4 as the photocatalyst has been disclosed (Scheme 24) [67]. According to the authors, the irradiation of the photocatalyst (Acr+-Mes) A with a blue LED leads to the excited state (Acr·-Mes·+) B. The aliphatic carboxylic acid 66 is converted by deprotonation to the corresponding carboxylate, which is

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

• our laboratory, we have explored the synthesis of 3,3,3-trifluoro- and 2,3,3,3-tetrafluoro-N-substituted propanamides, contributing to the field of fluorinated amides [25]. We have also investigated deprotonation at the α position of other fluorinated carbonyl derivatives as a route to new building

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

• from 6 on reacting with arynophiles 14 (Scheme 5) [59]. The reaction is unique due to its ability to functionalize position 3, despite its greater steric hindrance compared to position 5. The process involves deprotonation at the 3-position of the aryl(Mes)iodonium salts, followed by exit of a leaving

• intermediate I. Furthermore, intermediate I subsequently undergoes another SET reaction, resulting in intermediate II and the regeneration of the photocatalyst. Intermediate II undergoes deprotonation, facilitated by the presence of Cs2CO3 as base, to yield the final products 27 or 29. Additives like BQ likely

• assist in the deprotonation of intermediate II to produce final products 27, while K2S2O8 aids in the oxidation of the photocatalyst in the case of pyridine N-oxide. In another photoinduced reaction procedure, Murarka et al. reported the formation of aryl radicals from a tetrameric electron donor

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

• 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

• isolating the low-boiling non-polar products. Mechanistic studies suggested that in situ-generated difluorocarbene reacts with the ketone oxygen, followed by intermolecular protonation/deprotonation. Although the process has still synthetic limitations, also acyclic ketones can now be converted into

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

• activate alcohols presents a significant synthetic challenge. The carbazate substrates are easily prepared from ubiquitous alcohol precursors. The first stage of the transformation involves the sequential anodic oxidation of the carbazate and subsequent deprotonation to form a diazenecarboxylate. Further

• subsequent C–H abstraction. The methylarene undergoes oxidation, deprotonation, and a second oxidation before being captured by MeOH to produce a monomethoxylated product. This intermediate then undergoes a second oxidation round to yield the final product. Additionally, the same group disclosed an aromatic

• direct activation of C(sp3)–H bonds under mild conditions [17]. The pronounced electron-deficient W2C nanocatalysts greatly facilitate the direct deprotonation process, ensuring the longevity of the electrode by overcoming self-oxidation. The LSF of drug molecules such as ibuprofen methyl ester and

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

• ) [23][24][25]. The nucleophilic attack of the nitrogen atom on the oxidized C=C double bond results in the formation of a radical intermediate after deprotonation. This radical intermediate can proceed through various pathways (e.g., HAT, oxidation) to yield the desired final product. In the

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• amide at both the oxygen and the nitrogen, however, the ΔG‡ value for the latter was lower by 2.5 kcal·mol−1. This demonstrates a clear kinetic preference for formation of the five-membered ring over the seven-membered one [19]. Subsequent deprotonation of 11 leads to tertiary amide 12. Upon cyclization

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• products was concluded by the observed NOESY cross peaks between H2-H4 and H3-H4, clearly demonstrating the relationship between these three hydrogen atoms as cis. Formation of syn,syn-7a and -7b by the above tertiary amines would be mechanistically elucidated by the deprotonation of the most acidic H2

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• synthesised from the respective cis and trans-butenes by deprotonation followed by reaction with triisopropylborate [27], therefore the presence of E isomer in the Z-product 30 cannot be excluded. Chiral BINOL-derived phosphoric acids have been known since the 1970s as industrially relevant chiral counterions

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• acceleration of the reaction progress [26][27]. The crucial enhancement of anion stabilization by deprotonation of the methylene group in bisthiomalonates was hypothesized to surpass that of analogous dibenzyl malonate [28][29]. Surprisingly, the employment of NaH, NaSEt, or t-BuOLi as relatively strong bases

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

• physicochemical descriptors. A prominent early example are Hammett parameters, developed in 1937 [26][27], that relate substituent parameters to the equilibrium constant of the deprotonation of a substituted benzoic acid. The derived substituent parameters are used to gain insight into the mechanism of reactions

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• Scheme 2 but is open to debate. Thus, formamide adds to the [D1]-aldehyde A to form hemiaminal B which eliminates D2O to give imine D. Deprotonation of formamide D forms the resonance and zwitterrion-stabilized isocyanate E [22]. We then hypothesize that zwitterion E rearranges with loss of CO2 to form

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• carbocation of I produces intermediate II, which converts into intermediate III through a deprotonation–protonation process. Finally, the elimination of PhNH2 from intermediate III occurs to afford the desired product 2a. In the presence of NaOH, the Michael addition between 1a and base initially occurs to

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

• acetylacetonate 20. Extension of the sequence by cyclization with hydrazine leads to the pyrazole products 21 (Scheme 5) [53]. The method works best with acetylacetonates, since deprotonation of other diketones with NaOEt leads to deactivation of the isothiocyanates. A limitation of the method is the formation of

• . The α,β-unsaturated carbonyl compounds 60 can undergo cyclization with tosylhydrazine in situ to form pyrazoles 61 under alkaline conditions, with the tosyl group acting as a leaving group. Upon deprotonation at position 1 by a base, followed by nucleophilic substitution of halides, N-functionalized

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

• , our methodology involves a biphasic reaction medium where the starting material, viz. arylidenemalonate, remains in the organic layer and prevents itself from undergoing saponification because it requires either aqueous or alcoholic (MeOH or EtOH) medium. Furthermore, deprotonation of curcumin

• ). Unfortunately, no reaction occurred with aliphatic valeryl derivate 2h, presumably due to the competitive deprotonation of the active methylene group of curcumin and the allylic γ-position of the diester and/or the +I effect of the alkyl group which deactivates the β-position of the diester (Table 2, entry 8

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• formation of dimeric side products. Cyclic voltammetry analysis suggested an initial anodic single electron transfer (SET) to radical cation 5, cyclization and deprotonation. Subsequent SET oxidation in solution by 5 led to cation 7. Final deprotonation furnished aromatic cycle 4. In 2022, Zhang et al

• hydrazones initiated with the SET anodic oxidation of the hydrazone and deprotonation to form the N-centered radical 10. After aza-cyclization on the aromatic ring, a second SET oxidation and deprotonation delivered the heterocycle 9. This mechanism was supported by cyclic voltammetry analysis of a model

• point of view, the authors proposed the formation of N-pyridyl radical 18 through the anodic oxidation of in situ-generated anion 17. Subsequent radical cyclization, second anodic cyclization and deprotonation yielded the fused heterocycle 16. Similarly, Youssef and Alajimi disclosed the electrochemical

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

• negligible. These data suggest that deprotonation occurs prior to alkylation and that deprotonation of either indazole tautomer leads to anions of identical or highly similar energy. Furthermore, as seen in Figure 4, a total, five coordinated complexes were found to be at least 4.5 kcal/mol more stable than

• system (Figure 10). Under conditions A, deprotonation and cesium coordination were heavily favored by 11.1 kcal/mol (18(N-H)). Transition states 18-N2-Cs and 18-N1-Cs were found leading to N1- and N2-products, respectively. NCIs between the cesium cation with the ester and sulfonate oxygens, and

• 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

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• deprotonation with sulfamate, gives the 4-substituted isoquinolinone derivative 2a (Scheme 6). Looking into the formation of 2c' from 1c (Scheme 2), two other resonance structures for the initially formed intermediate 1CC, namely 1CC' and 1CC'', are shown in Scheme 7. The oxygen atom in the amide motif of the

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• make oxidation of amines less anodic (due to the H-bonding and facilitation of deprotonation of the radical cations), thus narrowing the potential gap. Preparative experiments were performed under the same conditions as described above: A one-compartment cell, DMF, 0.25 mol equiv of a mediator was

• contained some other compounds, which have not been identified. Among the amines studied, amine A3 is less prone to oxidation (due to the electron-withdrawing effect of the trifluoromethyl group) and is the less basic; the presence of a lutidine base even more fastens deprotonation of the radical cation