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

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

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• skeletal rearrangement, providing the distinct skeleton of 11 via carbocation C. This rearrangement involves the preferential migration of an alkenyl group in C to the carbocation, followed by deprotonation at C18 to form an exo-olefin. β-face-selective hydroxylation at C12 in 11 by the P450 enzyme BscG

• deprotonation to form exomethylene. Subsequent in situ removal of the silyl protecting groups led to the total synthesis of brassicicene K (27). Thus, the biosynthetic proposal featuring the Wagner–Meerwein-type skeletal rearrangement (9→11) through the catalysis of P450 enzyme BscF was successfully emulated by

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• . Additionally, stereoselectivity can be achieved by using potassium bis(trimethylsilyl)amide for deprotonation and methylation with MeI [33][39]. Any of these routes would yield methylated amino acids that can then be incorporated into an oligopeptide in solid-phase peptide synthesis (SPPS). Additionally, N

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• at 298.15 K. Following the approach of the Grzybowski group [3], we compute the heterolytic dissociation energy through the direct deprotonation reaction, ; see Equation 1. For each set of deprotonated C–H sites in a molecule, we determine the minimum heterolytic dissociation energy (). Hereafter, we

• use an out-of-sample dataset of 1043 pKa-dependent reactions from Reaxys, containing 584 aldol, 408 Claisen, and 51 Michael reactions. These reactions are chosen because they all involve a deprotonation step, and the C–H site with the lowest pKa value is most likely the site of the reaction. We also

• ML models predict the site of reaction using the lowest ML-predicted pKa value. To understand the result for the out-of-sample set, we show three different reactions in Scheme 1. The first step of the reaction shown in Scheme 1a is an aldol reaction where the deprotonation occurs at the least

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• were investigated in aqueous medium. An aqueous solution of 5.0 wt % DA11 in Milli-Q water was prepared, followed by deprotonation with 1.0 equivalent of NaOH, showing excellent solubility up to 93 mM, giving a deep purple solution. An aqueous 43 µM solution DA11, diluted from the 5.0 wt % stock

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• -4–Br. The next step is a deprotonation assisted by the released Br3Al–OAc species. This allows the formation of the AcO–AlBr2 salt via TS3–Br and the trans intermediate I-5–Br, which contains a Br–I(Ph)–O–naphthyl bond of 2.14 Å length. The last step is the bromination of I-5–Br by isomerization to