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

• four-step process involves allylation, Claisen rearrangement, isomerization, and oxidative dimerization. Each reaction step was optimized independently by using either online HPLC or in-line benchtop NMR spectroscopy to afford an overall yield of 67% in 66 iterative experiments over four linear

• convenient methodology for global optimization, eliminating the necessity of a theoretical model. A reconfigurable automated flow platform integrating online HPLC monitoring was used for the cobalt-catalyzed aerobic oxidative dimerization of desmethoxycarpacine (6) to carpanone (7) in the presence of oxygen

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

• final peroxide 157: recombination of radical C with tert-butylperoxy radical D or oxidation of radical C to carbocation E, which is nucleophilically attacked by TBHP. β-Peroxy ketones 159 were synthesized via oxidative dimerization of styrenes 158 using the Cu(I)/TBHP system (Scheme 50) [42]. The

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• material in Europe (Scheme 1). It is obtained by extraction and isolation of the colorless indole-O-glycoside indicane which is then hydrolyzed to give indoxyl. The latter undergoes oxidative dimerization to provide indigo. In the 19th century, syntheses of indigo were developed which made the pigment

• precursors. The base-mediated reaction of 5-chloroanthranilic acid (8a) with chloroacetic acid afforded 8b (Scheme 5) [20]. Acetylation and base-mediated cyclization gave indoxyl 9a which was transformed to indigo 1c by oxidative dimerization. Benzylation finally afforded 1d. 4,6-Benzylidenation of ᴅ

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

• %. Silyl deprotection with (n-C4H9)4NF in THF followed by acetylenic oxidative dimerization under Hay conditions produced the desired DBA 5 in 12.7% yield. It should be noted that a thermodynamically more stable trimeric macrocycle was also formed in 17.7%, but it was not isolated and purified because it

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• simple oxygen atmosphere (Scheme 1a) [30][31][32]. Most recently, we also showed that phenotellurazines could catalyze the oxidative dimerization of indoles, likewise under a simple oxygen atmosphere. 2-Methoxyphenotellurazine PTeZ2 proved to be the optimal catalyst in the latter case (Scheme 1b) [33

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene

• Semyon V. Tsybulin,
• Ekaterina A. Filatova,
• Alexander F. Pozharskii,
• Valery A. Ozeryanskii and
• Anna V. Gulevskaya

Beilstein J. Org. Chem. 2023, 19, 674–686, doi:10.3762/bjoc.19.49

• two 7-(arylethynyl)-1,8-bis(dimethylamino)naphthalene fragments was prepared via the Glaser–Hay oxidative dimerization of 2-ethynyl-7-(arylethynyl)-1,8-bis(dimethylamino)naphthalenes. The oligomers synthesized in this way are cross-conjugated systems, in which two conjugation pathways are possible: π

• oligomers 5 can be synthesized by a Glaser oxidative dimerization of monomers 6 (Scheme 1). The obvious route for the synthesis of the latter is the sequential alkynylation of 2,7-diiodonaphthalene 8. In accordance with this strategy, diiodide 8 was cross-coupled with copper(I) arylacetylides (Castro

• recrystallization of the crude product from ethanol. Next, the oxidative dimerization of terminal alkynes 6a–e was carried out in an aerobic medium in the CuI/TMEDA/iPr2NH system at room temperature, which proved to be effective in the synthesis of butadiynes 1–4 [15] (Scheme 3). The desired diarylbutadiynes 5a–e

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

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

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• )-1-benzylpyrrolidine-2-carboxamide) and its Ni(II)–Schiff base complexes formed of glycine, serine, and dehydroalanine are reported. A bulky tert-butyl substituent in the phenylene fragment precludes unwanted oxidative dimerization of the Schiff base complex, making it suitable for targeted

• be shown below, this is not necessary since the isomeric Schiff base template proved efficient in stereoselective modification of amino acids. The products of the oxidative dimerization via the phenylene ring were not detected for both isomeric templates. The subsequent reaction with (S

• the following problems. First of all, radical cations formed under a one-electron electrochemical oxidation of the glycine and dehydroalanine complexes become sufficiently stable. The fast side reaction of the oxidative dimerization of the Schiff base complex via the phenylene fragments (inherent to

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• the total synthesis of (−)-psychotriasine (202), (−)-calycanthidine (203), and (−)-chimonanthine (204). Synthesis of structurally diverse lignans (Zhu, 2022) [103]: Lignans are structurally diverse natural compounds generated biosynthetically by the oxidative dimerization of phenylpropanoids [104

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• heterocyclizations. Electrochemical N-ammonium ylide-catalyzed CH-oxidation. Oxidative dimerization of aryl- and alkenylmagnesium compounds catalyzed by quinonediimines. FLP-catalyzed dehydrogenation of N-substituted indolines. Funding This work was supported by the Russian Science Foundation (Grant no. 21-13-00205).

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• synthesis and utilization of derivatives of 4H-benzo[b][1,4]thiazine-3-carboxylic acid. These benzothiazine compounds were assembled via the coupling of aminothiols and bromopyruvates. Oxidative dimerization of these starting materials was also observed and the corresponding benzothiazine dimers were

• isolated. Moreover, the coupling of benzothiazines with amino acids was realized. In doing so, an enantioselective synthesis of the nonproteinogenic amino acid 2-amino-3-propylhexanoic acid was accomplished. Keywords: amino acid; benzothiazine; oxidative dimerization; peptide coupling; stereoselective

• %, respectively, under different conditions (Table 1, entries 3 and 4). Reactions in ethanol under MWI and in CH2Cl2 with classical stirring at room temperature only resulted in oxidative dimerization, forming derivative 11b in 15–28% yield (Table 1, entries 5–7). Neither did the reaction proceed in ethyl acetate

Breakdown of 3-(allylsulfonio)propanoates in bacteria from the Roseobacter group yields garlic oil constituents

• Anuj Kumar Chhalodia and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 569–580, doi:10.3762/bjoc.17.51

• labelling into dimethyl disulfide (DMDS), the oxidative dimerization product from MeSH, showing the activity of the demethylation pathway in these bacteria. However, knockout of the dmdA gene in R. pomeroyi still gave a low incorporation of labelling into DMDS, suggesting the presence of another gene

• the demethylation pathway that is fully established in P. inhibens by genes coding for DmdA–D (Scheme 4A). In the presence of air thiol 13 can then undergo an oxidative dimerization, or react analogously with MeSH to form allyl methyl disulfide (30, Scheme 4B). Similar oxidations requiring one

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• have attempted various combinations of Ti(IV) and reducing agents but Cp2TiCl2 with Zn powder provided the better results compared to the other combinations [14][40]. Additionally, they prepared benzyl–benzyl coupled sumanene dimer 48 by means of oxidative dimerization via sumanenyl monoanion

The biomimetic synthesis of balsaminone A and ellagic acid via oxidative dimerization

• Sharna-kay Daley and
• Nadale Downer-Riley

Beilstein J. Org. Chem. 2020, 16, 2026–2031, doi:10.3762/bjoc.16.169

• Sharna-kay Daley Nadale Downer-Riley Department of Chemistry, The University of the West Indies, Mona, Jamaica 10.3762/bjoc.16.169 Abstract The application of oxidative dimerization for the biomimetic synthesis of balsaminone A and ellagic acid is described. Balsaminone A is synthesized via the

• oxidative dimerization of 1,2,4-trimethoxynaphthalene under anhydrous conditions using CAN, PIDA in BF3·OEt2 or PIFA in BF3·OEt2 in 7–8% yields over 3 steps. Ellagic acid is synthesized from its biosynthetic precursor gallic acid, in 83% yield over 2 steps. Keywords: balsaminone A; biomimetic synthesis

• ; ellagic acid; oxidative dimerization; Introduction Over the last century, the formation of an aryl to aryl bond has garnered considerable synthetic attention due to the applications of biaryls as pharmaceutical agents, as well as chiral auxiliaries in asymmetric synthesis [1][2][3]. Methods such as the

Rearrangement of o-(pivaloylaminomethyl)benzaldehydes: an experimental and computational study

• Csilla Hargitai,
• Györgyi Koványi-Lax,
• Tamás Nagy,
• Péter Ábrányi-Balogh,
• András Dancsó,
• Gábor Tóth,
• Judit Halász,
• Angéla Pandur,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2020, 16, 1636–1648, doi:10.3762/bjoc.16.136

• Raney nickel (Ra-Ni), sometimes as the main product, depending on the activity of the catalyst [10] (Scheme 2). The oxidative dimerization of 1-phenylisoindole (6a) to compound 5a took place under various conditions: when refluxing in benzene in the presence of air [5][11], during an attempted

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• alkylation, reduction and catalytic hydrogenolysis, (+)-199 was converted to desired product (−)-200 with 80% ee (Scheme 62). An electrochemical method for the asymmetric oxidative dimerization of cinnamic acid derivatives was developed by Watanabe in 2016 [109]. The substrates for the electrochemical

• oxidation 201 were prepared from the corresponding cinnamic acids via condensation with ʟ-proline tert-butyl ester followed by ester hydrolysis. Upon oxidative dimerization under Ronlan’s electrochemical conditions, substrates 201 were converted to bislactones 202 with good enantioselectivity. The authors

Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones

• Keshaba N. Parida,
• Gulab K. Pathe,
• Shimon Maksymenko and
• Alex M. Szpilman

Beilstein J. Org. Chem. 2018, 14, 992–997, doi:10.3762/bjoc.14.84

• path to 1,4-dicarbonyl compounds. However, while oxidative dimerization of enolates is fairly straightforward [6][7], the coupling of two dissimilar enolates is contrastingly highly challenging. The more similar in steric and electronic properties the two dissimilar enolates become, the more difficult

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• catalytic amount of copper salt was required in this reaction. The hydrogens on the ortho and para positions of phenols have higher reactivity. Thus, undesired side reactions were often involved in the trifluoromethylation of less substituted phenols, including oxidative dimerization and oligomerization

Ni nanoparticles on RGO as reusable heterogeneous catalyst: effect of Ni particle size and intermediate composite structures in C–S cross-coupling reaction

• Debasish Sengupta,
• Koushik Bhowmik,
• Goutam De and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 1796–1806, doi:10.3762/bjoc.13.174

• and Ni/RGO-60) were also tested (Table 1). All reactions were carried out under a N2 atmosphere to avoid oxidative dimerization of thiols to disulfide [50]. Solvent optimization was started with water (Table 1, entry 1) followed by toluene (Table 1, entry 2) and isolating diaryl sulfide only 6–8

• suppressing the overall yield of the thioether (Table 1, entries 5 and 6). Without using any base, the yield was 74%, while the use of KOH as a base afforded the thioether in 83% yield (Table 1, entries 7 and 8). Formation of the diphenyl disulfide via oxidative dimerization of benzenethiol was noticed (15

Thiophene-forming one-pot synthesis of three thienyl-bridged oligophenothiazines and their electronic properties

• Dominik Urselmann,
• Konstantin Deilhof,
• Bernhard Mayer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2016, 12, 2055–2064, doi:10.3762/bjoc.12.194

• by a Sonogashira–Glaser sequence [74] also for probing delicate oxidative dimerization conditions with easily oxidizable phenothiazinyl moieties. According to our recent study on the formation of butadiynyl-bridged diphenothiazines [54] we were optimistic to probe this unusual approach. First, three

The marine sponge Agelas citrina as a source of the new pyrrole–imidazole alkaloids citrinamines A–D and N-methylagelongine

• Christine Cychon,
• Ellen Lichte and
• Matthias Köck

Beilstein J. Org. Chem. 2015, 11, 2029–2037, doi:10.3762/bjoc.11.220

• (18). Citrinamine A (1) is the 2,2´-didebromo derivative of mauritiamine (7) and as in the original publications of 7 and 18 no chiroptical effect was observed for 1. Synthetic studies on mauritiamine (7) [14] demonstrated the formation of similar racemic products by a chemical oxidative dimerization

Carboxylated dithiafulvenes and tetrathiafulvalene vinylogues: synthesis, electronic properties, and complexation with zinc ions

• Yunfei Wang and
• Yuming Zhao

Beilstein J. Org. Chem. 2015, 11, 957–965, doi:10.3762/bjoc.11.107

• oxidative dimerization reaction of corresponding dithiafulvene (DTF) precursors [27]. This straightforward C–C bond forming reaction has not only allowed TTFV derivatives with different substituents to be readily assembled, but served as an effective methodology to construct the π-conjugated frameworks of

• ]. This olefination reaction went completion within 3 hours to give DTF 4 in 77% yield after column separation. Compound 4 was then subjected to an oxidative dimerization in CH2Cl2 at room temperature using iodine as oxidant. The dimerization gave TTFV 5 as a stable yellow solid in 80% yield

Attempts to prepare an all-carbon indigoid system

• Şeref Yildizhan,
• Henning Hopf and
• Peter G. Jones

Beilstein J. Org. Chem. 2015, 11, 363–372, doi:10.3762/bjoc.11.42

• interactions. Our next approach towards 4 (or a derivative) started from indan-1-one (18, Scheme 4). Enolization of 18 was carried out with sodium hydride in THF and on subsequent oxidative dimerization the expected bis-ketone 19 was obtained. This compound is produced as a mixture of two diastereomers in

Building complex carbon skeletons with ethynyl[2.2]paracyclophanes

• Ina Dix,
• Lidija Bondarenko,
• Peter G. Jones,
• Thomas Oeser and
• Henning Hopf

Beilstein J. Org. Chem. 2014, 10, 2013–2020, doi:10.3762/bjoc.10.209

• The oxidative dimerization (Glaser coupling) of the achiral hydrocarbon 2 took place effortlessly and in high yield (Scheme 3). However, we have been unable so far to determine the exact structure of the isolated dimer. As shown in Scheme 3, in principle, two different dimers of 2 could be formed: one

• diastereomers are generated (as expected) by the oxidative dimerization of the mono ethynyl derivative [9], but assignment of the various spectra to specific stereoisomers remains an open question, and will only be possible after the resolution of the 4-ethynyl[2.2]paracyclophane, determination of its absolute

• configuration, and oxidative dimerization of an enantiopure sample. Glaser coupling of racemic 4 at room temperature yielded a mixture of diastereomeric dimers in good yield (67%) under the conditions shown in Scheme 4. Their gross structures follow from the spectroscopic and analytical data summarized in the

Rapid pseudo five-component synthesis of intensively blue luminescent 2,5-di(hetero)arylfurans via a Sonogashira–Glaser cyclization sequence

• Fabian Klukas,
• Alexander Grunwald,
• Franziska Menschel and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 672–679, doi:10.3762/bjoc.10.60

• ] employing the superbase system DMSO/KOH/H2O in the terminal cyclization step [33]. The same approach was applied to butadiynes that were formed by oxidative dimerization of arylalkynes with a Cu/Fe catalyst [34]. Apart from using reactive terminal alkynes as starting materials the major drawbacks of this

Zirconoarylation of alkynes through p-chloranil-promoted reductive elimination of arylzirconates

• Xiaoyu Yan,
• Chao Chen and
• Chanjuan Xi

Beilstein J. Org. Chem. 2014, 10, 528–534, doi:10.3762/bjoc.10.48

• , entry 8). When other diarylacetylene was employed in this reaction, the corresponding products were formed in 36% to 59% yields (Table 1, entries 9–12). No desired product was observed when alkylacetylenes were used. Recently, oxidative dimerization of alkenylcopper was reported to afford conjugated

• , 128.1, 128.2, 139.5, 140.4, 141.1, 142.0. Transformation of alkynes to olefins. Carbozirconation of alkynes via zirconacyclopentenes. TCQ-promoted reductive elimination of arylzirconate. TCQ-promoted arylzirconation of diphenylacetylene. Oxidative dimerization of 4a. Possible reaction mechanism