Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• yields of the products 3g and 3h. The more electron-withdrawing m-fluorophenyl (2i), o-chlorophenyl (2j), o-bromophenyl (2k), o-trifluoromethylphenyl (2l), and o-nitrophenyl (2m) groups also resulted in comparable yields of 3g–m, respectively, indicating no significant effect of substitutents on the aryl

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

• -amidyl radicals uses activated N–O amide derivatives capable of generating amidyl radicals through fragmentation [18][19]. The direct formation of amidyl radicals in the presence of a carbon alkyl chain could lead to a competitive 1,5-hydrogen atom transfer (1,5-HAT) [20][21][22], limiting the direct

• attack the radical cation A, giving the bicyclic radical intermediate B. Amide is an ambident nucleophile, and oxygen attack of radical cation A is also conceivable to give the corresponding imidate [28]. In our reaction, O-addition is disfavored due to the formation of an unsaturated four-membered ring

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

• was the five-membered prolinol 7a rather than the initially assigned isomeric seven-membered tetrahydrooxazepine 6 [16]. Subsequently, we set out to understand the O- versus N-chemoselectivity by DFT modelling, and to develop an effective synthetic protocol for the preparation of prolinols 7 in high

• 2019, we reported our DFT study on the cyclization of N-allylbenzamide (1a) to the 2-oxazoline 4a, i.e., where n = 1 and Ar = Ph [18]. This work indicated that the alkene is activated by the iodine(III) species and that this triggers cyclization. Intrigued by the change in mechanism from O- to N

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• interactions (X···O/N/S). For C–X, a σ-hole arises when a valence electron is pulled into the σ-molecular orbital resulting in an electropositive crown and a flattening of the atomic radius, that accounts for the directionality of the interactions [55][56]. Thus, the halogen has an amphoteric character with an

• electropositive halogen bond ability along the σ-hole (C–X···O/N/S, a ≈ 180°) and an electronegative hydrogen bond acceptor perpendicular to the C–X bond (C–X···H, a ≈ 90°) [57][58][59][60]. Such halogen bonds have been detrimental in the understanding interactions of organic halogens in biological systems [61

• ][62][63][64][65]. In our case, for compound 15, I4 interacts with H4 (d = 3.521 Å, a = 93.77°) and I4 also interact with the oxygen of the carbonyl of the acetate at C6 (I4···O, d = 3.147 Å; a = 179.70°) (Figure 4b and Table 7). This result is in line with hydrogen (C–I···H) and halogen (C–I···O

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

• decreased the chemical yields as well as the diastereomeric ratios (Table 3, entries 1–4). The higher pKa values of the carbonyl α-proton of 4 (for example, the pKa values of the protons of X-CH2C(O)Ph in DMSO were reported to be 17.1 (X: PhS) [45] and 20.3 (X: Ph2N) [46]) would result in the contamination

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• 10.3762/bjoc.20.205 Abstract Nitration of O-methylisouronium sulfate under mixed acid conditions gives O-methyl-N-nitroisourea, a key intermediate of neonicotinoid insecticides with high application value. The reaction is a fast and highly exothermic process with a high mass transfer resistance, making

• its control difficult and risky. In this paper, a homogeneous continuous flow microreactor system was developed for the nitration of O-methylisouronium sulfate under high concentrations of mixed acids, with a homemade static mixer eliminating the mass transfer resistance. In addition, the kinetic

• insecticides is increasing as the world’s food crisis intensifies due to the changes in the natural environment and ongoing geopolitical crises [1]. O-Methyl-N-nitroisourea (NIO) is a pivotal pesticide intermediate in the preparation of nitroguanidine derivatives, which are the raw material for highly

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

• Pt cathode and a Mg anode in the presence of carbon dioxide induced reductive C(sp3)−O bond cleavage at the benzylic position in diarylmethanol compounds and subsequent fixation of carbon dioxide to produce diarylacetic acids in good yield. This protocol provides a novel and simple approach to

• diarylacetic acids from diarylmethanol species and carbon dioxide without transformation of the hydroxy group into appropriate leaving groups, such as halides and esters including carbonates. Keywords: C(sp3)–O bond cleavage; diarylacetic acid; diarylmethanol; electrochemical reduction; fixation of carbon

• dioxide; Introduction Electrochemical reduction of benzyl alcohol derivatives can induce reductive cleavage of a C(sp3)–O bond [1] at the benzylic position to generate the corresponding benzylic anion species. This protocol has been frequently applied to electrochemical carboxylation [2][3][4][5][6][7][8

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• -triazole, thiazole, or pyridine were synthesized by the reaction of 3,5-di-tert-butyl-o-benzoquinone or 3,5-di-tert-butyl-6-methoxymethylcatechol with different heterocyclic thiols. The S-functionalized catechols were prepared by the Michael reaction from 3,5-di-tert-butyl-o-benzoquinone and the

• derivatives are used as ligands in the synthesis of metal complexes (Ni(II), Pd(II), Pt(II), Cu(I), Ag(I) etc.) exhibiting antibacterial and antitumor activity [34]. In most cases, polyfunctional catechol thioethers were obtained by Michael reaction via the interaction of o-, p-benzoquinone and the

• /prooxidant, and antiradical activity was carried out for the catechols synthesized in this work. Results and Discussion Synthesis The interaction of 3,5-di-tert-butyl-o-benzoquinone with the corresponding thiols in ethanol at room temperature under argon leads to the formation of catechol thioethers 1–3 (69

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

• 11. It was proposed, that the internal hydrogen bond between the catalyst 11 and the P=O fragment of the protecting group of imine 9 is responsible for the observed high enantioselectivities (76–98% ee). The scope included a wide range of substrates, such as aromatic, heteroaromatic, aliphatic, and α

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• -step synthesis. However, in comparison to the DMP-tag or AzidoTMT the release of the reporter ion from the SOX-tag has somewhat lower intensity. Calle et al. designed, synthesized, and validated a series of ‘clickable’ linkers for characterization of protein O-glycosylation containing positively

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• ), Koser’s reagent (PhI(OH)OTs), Zhdankin’s reagent (C6H4(o-COO)IN3, ABX), and Dess–Martin periodinane (DMP) – and find application in an array of synthetically important transformations including olefin difunctionalization, carbonyl desaturation, alcohol oxidation, and C–H functionalization [3][4

• challenging iminoiodinanes). In situ preparation of the iminoiodinane intermediates is possible, and for those reagents that undergo facile decomposition, aziridination is more efficient using these conditions (yields for in situ-generated iminoiodinanes are in parentheses in Scheme 3, with N-o-methyl (6g

• of HFIP (Scheme 4). First, 1H NMR was employed to examine the interaction between HFIP and iminoiodinane 2c in CD3CN (compound 2c was chosen over 2a due to its increased solubility in nonprotic solvents). In a sample of 2c with 4 equivalents of HFIP, a broad signal for O–H proton of HFIP was observed

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

• method to prepare [D1]-formamides (D–C=O) is through a Leuckart–Wallach reaction with an amine and [D1]-methyl/ethyl formate or [D1]-dimethylformamide [19][20]. Stockmann and co-workers produced [D2]-formamides (N–D, D–C=O) via acid-catalyzed nitrile hydrolysis with HCl and D2O [21]. Thus, using the

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• substrate for gem-difluorination to yield the difluorinated compound 2e (Table 2, entries 8 and 9). Interestingly, terminal alkynes bearing –OH and –O– functional groups, such as 1f and 1g, were used for reactions, and the corresponding products 2f and 2g were obtained by both methods (Table 2, entries 10

Synthesis and reactivity of the di(9-anthryl)methyl radical

• Tomohiko Nishiuchi,
• Kazuma Takahashi,
• Yuta Makihara and
• Takashi Kubo

Beilstein J. Org. Chem. 2024, 20, 2254–2260, doi:10.3762/bjoc.20.193

• O–O bond cleavage to give compounds 1 and 5 (Scheme 2). Owing to the high reactivity of the DAntM radical, cyclic voltammogram (CV) was measured by using the stable DAntM cation, prepared from compound 3 oxidized by antimony(V) chloride, which can be characterized by 1H, 13C NMR, and UV–vis

• formation of a 1,2-dioxetane (DOT) intermediate and decomposition to aldehyde 1 and anthroxyl radical 5 via C–C and O–O bond cleavage. This reactivity is attributed to the predominant localization of an unpaired electron at the central sp2 carbon of the DAntM radical. These findings provide variable

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• recorded on a JASCO FP-8500. All calculations were carried out using the Gaussian 16 program [21]. The DFT calculations were carried out using the long-range and dispersion-corrected ωB97X-D functional [22]. The 6-31G(d,p) basis set was used for H, C, O, and S atoms [23][24]. The solvent effect of CH2Cl2

• , 82.18, 66.30, 53.55, 31.39, 28.42, 25.54, 22.48, 13.98; FTIR ν (cm−1): 2067 (C≡C), 1730 (C=O); MALDI–TOF MS (dithranol, m/z): [M]+ calcd for C62H70N6O8, 1026.53; found, 1026.98. Previously reported regioselective double azide addition to DBA with hexyloxy substituents and molecular design in this study

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

• of acetone and amines 2 leads to the formation of acetone imine/enamine (reaction 1, Scheme 6). Nucleophilic addition of an enamine to the most electron-deficient carbonyl group (C1=O, adjacent to the EWG) of the 1,3-diketones 1 gives the acyclic carbinol I (reaction 2, Scheme 6), followed by the

• intramolecular addition of enamine I to the C3=O to form intermediate II, which dehydrates to cyclic carbinol III. Finally, dehydration of intermediate III yields anilines 3. Conclusion In summary, a method for the synthesis of substituted meta-hetarylanilines under mild conditions starting from 1,3-diketones

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

• 9-O-methyl ether, altenusin, dehydroaltenusin, altertenuol, and altenuene) were frequently found and isolated as fungal contaminants in food and feed and have been investigated in significant detail, further metabolites, which were much more rarely found as natural products, similarly show

• the parent alternariol (1, 1099 publications given in the SciFinder database at 04/2024), 9-O-methylalternariol (2, 578 entries), altenuene (54, 320), altenusin (47, 130), dehydroaltenusin (74, 55), altertenuol (31, 45), and isoaltenuene (55, 24), where the most abundant Alternaria toxins are usually

• abbreviated: Alternariol (AOH), 9-O-methylalternariol (AME), altenuene (ALT), and altenusin (ALS) have commonly accepted abbreviations, while further abbreviations are used inconsistently (e.g., iALT or isoALT for isoaltenuene). Alternaria metabolites [7][9][10][11] (which not only consist of the herein

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO2-containing analogue of anticancer drug-candidate enastron (SO2 vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions – synthesis

• signals clearly corresponds to the heterocycles depicted above. Figure S8 (see Supporting Information File 1) shows 1H NMR spectra for Ph-substituted O,S,Se-DHPMs 2a,h,o. It can be seen from them that when going from oxygen to selenium (2h→2a→2o), the signals of both NH groups shift to down field (7.87

• /9.26→9.75/10.50→10.26/10.85 ppm) and become more equivalent (Δδ = 1.39→0.75→0.59 ppm accordingly). The key signal in the 13C NMR spectra is located in the regions 174.04–174.69 ppm (C=S), 151.44–151.86 ppm (C=O), and 170.15–170.91 ppm (C=Se) accordingly. Utilization of reaction products The Biginelli

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• -Addition of molecular bromine to phenyl isocyanide was reported by E. Kühle et al. to afford the corresponding 1,1-adduct (PhN=CBr2) [23]. Since dichloro compounds (RN=CCl2) [24] are the imino derivatives of highly toxic phosgene (O=CCl2), reactions using them as key intermediates are not safe synthetic

• lack of geometrical isomerization of the C–N double bond of the dithiolation products [32]. The thioselenation product 6’, an imine derivative, can be converted to a β-lactam derivative by [2 + 2] cycloaddition with ketene generated in situ. For example, thioselenation of RNC (R = (EtO)2P(O)–CH2) gave

• acid [58]. Rainier et al. reported the thiol-mediated 5-exo cyclization of o-alkynylaryl isocyanides, which successfully afforded dithiolated indoles 22 (Scheme 15) [59]. However, depending on the reaction conditions, quinoline derivatives were also produced as byproducts (vide infra). The photoinduced

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• glycosylation: i) N-glycosylation, where a N-acetylglucosamine (GlcNAc) is linked to the nitrogen atom of an asparagine side chain [28]; ii) O-glycosylation, where a GlcNAc or N-acetylgalactosamine (GalNAc) is linked to the hydroxy group of a serine or threonine residue [29]; iii) C-glycosylation, where a

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

• substrates according to this method. However, attempts to carry out the reaction sequence with unprotected hydrazine were unsuccessful. Alternatively, Mitsunobu reagent 23 can be reacted with in situ generated benzyne (from o-(trimethylsilyl)phenyl triflate) to provide the hydrazides for the concomitant

• formation of alkenone intermediates, dialkyl acetylenedicarboxylates 147, as alkynoyl derivatives, are transformed to pyrazolones 149 by Michael addition–cyclocondensation with phenylhydrazine. In a consecutive one-pot reaction, the latter intermediates undergo O-acylation with aryl chlorides to give N

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• before being introduced into the photoreactor (volume: 1.0 mL) (Table 1, top right). After several trials, we decided to fill syringe A with o-alkynylacetophenone 1a and syringe B with AgNTf2, P(4-CF3C6H4)3, benzyltrimethylsilane (2a, TMSBn), and TFA (see Supporting Information File 1 for details). At

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• -iodobenzoate. Under similar conditions, 4-nitroiodobenzene produced exclusively the corresponding homocoupling product 4,4’-nitrobiphenyl. Additional author remarks Other attempts to utilize 1,2-difluoroethylene in reactions with N-, O-, and C- nucleophiles carried out in our group were unsuccessful [78

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

• % at room temperature to 89% when warmed to 50 °C. No information was provided to justify any N2-selectivity or the lack thereof. Should an N2–Cs+–O ion pair exist, this could reasonably account for all the reported results presented herein (vide infra). Additionally, using Cs2CO3 in dioxane provided

• OPPh3 contributing to the increased error and standard deviation. Compound 6 was completely consumed and not detected (see Supporting Information File 1). Mechanistic considerations Alam and Keeting proposed a deprotonated intermediate that utilized the indazole N2 and C=O from an ester substituent at C

• the N1-product with highly similar energy (averaging −16.8 kcal/mol). The N2-s-cis and N2-s-trans TSs leading to the N2-product were higher in energy and led to the higher energy N2 products. The critical difference between N1-s-cis and N2-s-cis is the presence of the N2–Cs+–O non-covalent interaction

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• acetate 2i in high yield. A similar result was obtained for the furanyl derivative 2j. Pyrazoles were the only substrate class which clearly benefited from light irradiation (2k–o), displaying not just a shorter reaction time but also higher yields. Even unprotected pyrazoles (2k, 2m, 2n) performed well