Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• reflectance probe was employed for real-time monitoring of hydrolysis by in-line UV–vis spectroscopy. The raw data was processed using a sophisticated neural network algorithm, yielding rapid quantification with an impressive processing time of 1.4 ms per spectrum. This streamlined approach ensured efficient

• and timely data analysis, facilitating seamless real-time monitoring of the hydrolysis of 16. The final hydrogenation step was monitored by an in-line IR probe. The spectral data was processed using a partial least squares regression model and quantified. An online UHPLC was used to analyze the final

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• formation reaction. Pleasingly, benzo[j]fluoranthene 27 was obtained successfully via the Pd-catalyzed reaction of dibromonaphthalene 14 and naphthylboronic ester 26 in DMSO at 120 °C, albeit in a modest yield of 34%. A final basic hydrolysis of the acetoxy group furnished benzo[j]fluoranthene 23 bearing a

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

• , and with bulky substituents, the reaction did not proceed. Further derivatizations of the products were carried out: firstly, the derivative 35e was reduced using NaBH3CN to obtain 36 as a single diastereomer in a good yield. Next, a hydrolysis of 36 using concentrated sulfuric acid led to the 1,2

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• complex, which facilitates the cleavage of the N–O bond and subsequent 1,3-cyclization, ultimately leading to the formation of 2H-azirine. Therefore, the isomerization of isoxazole 1j was carried out at a higher temperature, 82 °C, but after hydrolysis of the reaction mixture, instead of the expected

• azirine dicarboxylic acid 6j, oxazole-4-carboxylic acid 9 was isolated. Apparently, azirine 2j underwent ring opening at higher temperature to nitrile ylide 7, which after cyclization and hydrolysis gave acid 9 (Scheme 3) (cf., e.g. [23]). Next, given that the preparation of 2H-azirine-2-carboxamides from

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• megaenzyme machinery. Water can act as the nucleophile during the offloading step, which amounts to hydrolysis and results in a linear peptide. On the other hand, a cyclic peptide forms when an intramolecular functional group acts as the nucleophile in this step. Regardless of the resulting topology, the NRP

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• . After metalation with Ni(acac)2 and hydrolysis electron-rich porphyrins were obtained, that are equipped with covalently attached long chain acid substituents. The target compounds have potential applications in catalysis, sensing, and materials science. The fluorinated aliphatic carboxylic acids (TfO

• porphyrins with Ni(acac)2; c) ester hydrolysis to generate the free acids 32, 33, and 34. Conditions: a) 1) 22/23/24, TFA, abs. DCM, N2, reflux, 30 min, 2) pyrrole, reflux, 2.5 h, 3) DDQ, reflux, 2 h; b) Ni(acac)2, toluene, reflux, 20 h; c) 1) LiOH, MeOH, rt, 1 h, 2) HCl. Supporting Information Supporting

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• stability than boronic acids and other employed esters as the four methyl groups protect the boron center from attack of water [44][45], preventing protodeboronation from the hydrolysis route. However, protodeboronation can be complex when it comes to pKa considerations, for example, 3,5

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• a smooth [1,3]-proton shift reaction with a high chirality transfer, affording the corresponding rearranged products in acceptable yields. Without purification, these products were subjected to acid hydrolysis and the subsequent N-Cbz protection, providing the optically active tetrafluoroethylenated

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• product 6 was not observed. Instead, among the several side-products formed, we were able to isolate α-aminoamidine 7, as the result of a 3C Ugi-type reaction between an aldehyde obtained from an oxidation–hydrolysis process of compound 5, tert-butyl isocyanide and 2 equivalents of aniline, and the

Efficient modification of peroxydisulfate oxidation reactions of nitrogen-containing heterocycles 6-methyluracil and pyridine

• Alfiya R. Gimadieva,
• Yuliya Z. Khazimullina,
• Aigiza A. Gilimkhanova and
• Akhat G. Mustafin

Beilstein J. Org. Chem. 2024, 20, 2599–2607, doi:10.3762/bjoc.20.219

• as 6-methyluracil (MU), 1,3,6-trimethyluracil (TMU), and pyridine (Py), and the results of the experiments are presented in this article. The hydroxy derivatives of MU and Py, obtained through oxidation followed by acid hydrolysis, possess compelling biological properties, rendering them practically

• 2 was no more than 15%. Subsequently, upon acid hydrolysis of compound 2, HMU (3) was produced. The addition of PcM to the reaction mixture resulted in a significant increase in the yield of compound 2 [13][22]. The catalysts were added in quantities ranging from 0.00001–0.1 wt %, with the amount of

• derivatives). Our study marks the first time pyridine has been involved in the peroxydisulfate oxidation reaction. The oxidation of pyridine (7) using APS resulted in a single product – pyridin-2-yl ammonium sulfate (8). Upon acid hydrolysis, this product yielded HPy (9, Scheme 2). The physicochemical and

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

• . Mechanistically, this transformation can be understood as follows: first, a Br/Cl/CF3 radical is formed via anodic oxidation, which subsequently attacks the olefin. The newly formed benzyl radical is oxidized to a carbocation, which undergoes nucleophilic attack by DMF. Hydrolysis of the imine delivers the final

• method for the hydrolysis of hydrosilanes to silanols using N-hydroxyphthalimide (NHPI) as the hydrogen-atom-transfer (HAT) mediator [38]. To demonstrate the potential of their approach, they showcased the LSF of natural products such as (−)-borneol and (+)-fenchol, as well as pharmaceutical drugs

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

• et al. [22] have demonstrated a combined use of flow and batch processes involving an electrochemical flow cell for the oxidation of furfuryl alcohols and subsequently utilizing the crude electrolysis mixture for hydrolysis in a traditional batch process to get the rearranged Achmatowicz product. As

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

• detection of benzaldehyde which was considered to be formed by the NaClO-mediated oxidation of benzyl alcohol generated by hydrolysis. Changing the oxidizing reagent to crystalline NaClO·5H2O nicely solved the problem with the realization of 86% isolated yield of 2b by the utilization of this oxidant (2

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

• -diaminonaphthalene derivatives 42, which after hydrolysis and extraction into toluene, were reacted with indole, 3-methylindole, 3,4-dihydroisoquinoline, and benzoyl hydrazone ethyl glyoxylate ester to afford terminal (E)-trifluoromethyl homoallylic amines 44 with up to 3 adjacent stereocentres with high to

• molecule. The BINOL catalyst 39 forming arylboronate species, enables the shift to occur asymmetrically. In the second step, the hydrolysis of unreactive diaminonaphthalene derivative 42 gives the poorly reactive and highly air-sensitive trifluoromethylallylboronic acid 43, but after the dehydration forms

• synthesis of homoallylic amines 117 and showed increased yields and enantioselectivities for aromatic aldehydes. In addition, a simple, ambient-temperature hydrolysis procedure was reported that yielded the unprotected analytically pure homoallylic amines in high yields without the need for chromatographic

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

• and PIDA [30][33]. During this experiment, a small amount of hydrolysis product 4-(trifluoromethyl)benzenesulfonamide was also observed (1.2 mM, signals at 8.0, 7.9, and 5.86 ppm), but this compound did not greatly contribute to the broadening of O–H proton signal of HFIP as a separate 4.0 mM sample

• mixtures of aziridines are obtained from aziridination reactions of cis- or trans-β-methylstyrene, suggesting aziridine formation likely to operate via a step-wise pathway. d) Aziridination is not impacted by the presence of potential radical traps. e) PhIO, potentially generated by PhINTs hydrolysis, can

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

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

• 5 was prepared from phthalimide (1, Scheme 1). Iodination followed by hydrolysis afforded 4,5-diiodophthalic acid (2) in 46.7% yield. Esterification with 1-hexanol yielded compound 3 in 56.8% yield and the subsequent Sonogashira coupling with trimethylsilylacetylene provided compound 4 in 80.0

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

• Haifeng Yu Wanting Zhang Xuejing Cui Zida Liu Xifu Zhang Xiaobo Zhao College of Chemistry, Baicheng Normal University, Baicheng, Jilin 137000, China 10.3762/bjoc.20.190 Abstract An eco-friendly selective hydrolysis of chain α-oxo ketene N,S-acetals in water for the switchable synthesis of β-keto

• thioesters and β-keto amides is reported. In refluxing water, the hydrolysis reactions of α-oxo ketene N,S-acetals in the presence of 1.0 equiv of dodecylbenzenesulfonic acid effectively afforded β-keto thioesters in excellent yield, while β-keto amides were successfully obtained in excellent yield when the

• hydrolysis reactions were carried out in the presence of 3.0 equiv of NaOH. The green approach to β-keto thioesters and β-keto amides avoids the use of harmful organic solvents, thiols and thiolacetates as well as amines, which could result in serious environmental and safety issues. Keywords: α-oxo ketene

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

• alternariol and 9-O-methylalternariol and the alternariol-9-O-sulfate (13–15) are conjugates repeatedly present in fungal sources [134][141][145] and the 3,9-O,O-disulfate of alternariol (16) has similarly been isolated [146]. Due to the instability of these sulfates towards hydrolysis they were typically not

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• showed that the activity of a difunctional organocatalyst in lactose hydrolysis was improved 5.2-fold by immobilisation on different solid supports that mimic the active site channels of enzymes [113]. In a solid-supported system, the solvent can exert a different influence on the catalytic activity

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

• radical, which induces 5-exo cyclization. The following hydrogen abstraction, intramolecular ionic cyclization, and hydrolysis during chromatography on silica gel affords the cyclic amide in good yield. They further applied this radical cyclization reaction as a key step in the synthesis of (±)-α-kainic

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

• -phenyl-2,4-hexanedione was generated in situ through acid hydrolysis of 1,1,1-trichloro-4-methoxy-6-phenyl-3-hexen-2-ones 71. Subsequent cyclization with hydrazine hydrochloride followed by hydrolysis of the trichloromethyl group led to 73. This intermediate was then reacted with 2,2,2-trifluoroethanol

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

• electrolyte with potassium carbonate as a base and two platinum electrodes. Mechanistically, condensation of the two reactants formed isatin-derived acylhydrazone 37. Hydrolysis of the latter in the presence of the inorganic base gave rise to potassium carboxylate 39. Meanwhile, two consecutive SET oxidations

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

• heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation–hydrolysis–reverse amidation protocol. Keywords: amino acids; DEL

• the most employed approach for producing this family of substrates [12]. Despite its effectiveness, this approach requires hazardous cyanides and harsh conditions for the subsequent hydrolysis of the nitrile or the hydantoin. Additionally, it carries significant limitations in its scope, reducing its

• proceeded smoothly yielding 4j in quantitative yield. However, obtaining compound 4r presented some challenges due to the resistance of ester 2r towards conventional oxidation methods (see Table S5 in Supporting Information File 1). Consequently, a multi-step process involving ester hydrolysis and

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• converted into the corresponding acids 4a,b by hydrogenolysis under mild conditions, which proceeded in quantitative yields (Scheme 4). It should be noted that this method of preparing β-lactam acids compares favorably with the alkaline hydrolysis of their methyl and ethyl esters, which does not always give