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

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• -lactone motif on an estradiol backbone [17]. Beginning with the 7α-alkanamidoestrone derivative 17, a nucleophilic addition by the anion of the THP propargyl ether occurred stereoselectively and provided the alkyne 18 in a 75% yield. Afterwards, the catalytic hydrogenation of the alkyne with a 1:1 mixture

• ether 39, a ring-closing enyne metathesis (RCEYM) was initiated using the Grubbs second-generation catalyst (G-II) and high temperature to obtain the spiro 2,5-dihydrofuran derivative 40 in 76% yield. Additionally, when a dienophile such as N-phenylmaleimide was directly added to the same pot and

• (110a and 110b, respectively). These protected compounds were subjected to alkynylation using 4-THPO-1-butyne on the carbonyl group at C-17, yielding steroids 111. Subsequent catalytic hydrogenation of the triple bonds, followed by deprotection of the alcohols from their THP ether groups and oxidation

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

• oxidation with the incorporation of a ketone at the C13 position yielded brassicicene A (23). After conversion of 23 into the corresponding silyl enol ether, Rubottom oxidation allowed completion of the total synthesis of brassicicene R (24). As an effort to explore the biomimetic rearrangement, analogous

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

• -desmethyl coibamide A in solution has been demonstrated by Sable et al. [43]. The use of diazomethane in diethyl ether as methylating agent yielded the methylated synthetic coibamide A. All of the aforementioned methods are robust and well-established. However, they do have their drawbacks. The application

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• ]. These RiPP natural products encompass a wide range of structural scaffolds including cyclopeptide alkaloids that contain a phenolic ether-linkage and the lyciumin-type peptides that are composed of a crosslink between the Trp-indole-N and the carbon in another amino acid side chain or peptide backbone

• . jasminoides that directly match this FFFY sequence (Figure 6A). Like other members of the Rubiaceae family [7][34], the tyrosine that forms the ether linkage remains intact, and not oxidatively decarboxylated as seen in members of the Rhamnaceae family. It is also predicted to contain a dimethylation at the N

• . argentea (Figure 4). Unlike moroidins which are part of the stephanotic acid subclass of burpitides defined by the Trp-indole-C to carbon crosslink, the molecules from the A. bettzickiana seems to be cyclopeptide alkaloids with two tyrosine derived ether linkages that resemble selanine A isolated from

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• temperature. The crude reaction mixture was purified by silica gel (230–400 mesh) column chromatography (petroleum ether/EtOAc as the eluent) to give the product 3 or ent-3. Selected examples of drugs and bioactive molecules bearing a pyrazole core. Single crystal X-ray structure of ent-3ba (CCDC 2234286

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• size of the alkyl side chain at the alpha position of arylacetic acids (9–16). These features offer great opportunities for the introduction of a wide range of functional groups, including bromide (9), boron (12), ether (13), nitrile (14), ester (15), and alkene (16) moieties, which are versatile

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• speculate that the solvation effect might be beneficial for stabilizing the condensation intermediate I and avoiding further unwanted conversions, e.g., nucleophilic attack of excessive benzylamine to the intermediate I. The following examination on solvents demonstrated that using ether solvents as the

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• one hour. After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography with a mixture of ethyl acetate and petroleum ether (v/v = 1:4) as eluent to give the pure product for analysis. Pentamethyl rel-(4R,4aR,4bS,8aS)-1-benzyl-8-cyclohexyl-4

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• Rouser et al. using an intramolecular Cannizzaro reaction to give the corresponding unsymmetrical acid–alcohol substituted crown ether derivatives 43–46. Good to excellent yields of the desymmetrized Cannizarro products 43–46 were obtained using Ba(OH)2 as the base, thus effecting efficient

• desymmetrization of crown ether dialdehydes (Scheme 17) [84]. Synthesis of natural products and pharmaceuticals Exploring intramolecular Cannizzaro reaction: The Cannizzaro reaction is a versatile synthetic tool with applications in the synthesis of natural products, fine chemicals, and pharmaceuticals. Its

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• presence of alkene, alkyne, halogen, and ether moieties. N-Boc-protected amines and esters also provided a good to excellent yield. Unfortunately, α,β-unsaturated carboxylic acids and aliphatic carboxylic acids were ineffective using this method. In 2024, Liu and co-workers [31] introduced a photocatalytic

• radical cation 81 and Mes–Acr because of the favorable π–π stacking. Ethyl vinyl ether, which is the most nucleophilic molecule in the reaction, combined with radical cation 81 to form the oxonium radical 82, which could proceed in two directions: 1) β-elimination, yielding radical 83 and 2) photoinduced

• breakdown of ethyl vinyl ether and trapping of ethanol, yielding radical 84. To regenerate the photocatalyst, PhSSPh functioned as an oxidant. After protonation upon the β-elimination step, PhS− contributed a hydrogen atom to both 83 and 84, alongside regeneration of the HAT catalyst. Lastly, the acetal

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• family members in bacteria and plants [4], these diterpenoids have four main structural differences: the number and location of oxidized carbons, the absence or presence of transannular ether bridges, the configuration (cis or trans) of the bicyclic ring fusion, and the presence and configuration (E or Z

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• precipitation with a hexane–ether mixture and was found to be of sufficient purity for spectroscopic analysis. If desired, the product can be crystallized from an EtOAc–MeOH mixture for further purification. On the other hand, compound 2a has also been previously investigated for its potential covalent prolyl

• transformations is the purification of the synthesized product, since these oils are non-volatile and non-polar. However, in this study, the choice of these materials as green solvents allows convenient isolation of the cycloadducts by precipitation followed by filtration with hexane or diethyl ether. Thus, IMDAF

• , the reaction mixture was cooled to room temperature and the desired product, 2a was precipitated after trituration with hexane. The obtained solid product was isolated by filtration under vacuum, washed with ether–hexane solvent mixture and dried at room temperature. If desired for further

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• two silyl enol ether moieties, can be regarded as masked dianions or electroneutral equivalents of 1,3-dicarbonyl dianions and react with the same regioselectivity [13][14][15][16][17][18][19][20][21][22]. Both free and masked dianions were studied extensively in my group for many years. 1,3-Bis

• (silyloxy)-1,3-butadienes are highly moisture sensitive compounds which can be prepared from the corresponding 1,3-dicarbonyl dianions in two steps. For example, diene 6a is available by silylation of 2 to give silyl enol ether 5 which is subsequently deprotonated by LDA and treated with

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• dioxide (15 mmol, 1.66 g). The reaction mixture was stirred under a nitrogen atmosphere at 80 °C for 3 h. Before the solvent was evaporated at reduced pressure using a rotary evaporator, TLC was performed to verify completion of the reaction using 7:3 petroleum ether/ethyl acetate as the eluent. Upon

• in a different round-bottom flask, and the solvent was evaporated in a rotary evaporator. The resulting solid was dissolved in DCM, and silica gel was added to the DCM layer. This slurry was subjected to column chromatography on silica gel (100–200 mesh) using petroleum ether and ethyl acetate as

• solid. The filtrate was evaporated and column-chromatographed on silica gel (100–200 mesh) using petroleum ether and ethyl acetate as an eluent. The initial yellowish orange fraction containing N1,N2-bis(2-methoxyphenyl)oxalamide, collected with 22% ethyl acetate, was recrystallized from a chloroform

Kinetically stabilized 1,3-diarylisobenzofurans and the possibility of preparing large, persistent isoacenofurans with unusually small HOMO–LUMO gaps

• Qian Liu and
• Glen P. Miller

Beilstein J. Org. Chem. 2024, 20, 1099–1110, doi:10.3762/bjoc.20.97

• product (23 mg). Finally, the crude product was purified by preparative TLC (petroleum ether/EtOAc 3:1) to give 27 as a yellow powdery solid (15 mg, 22%, 35% based on reacted 3, Scheme 8). Mp 180 °C (dec.); 1H NMR (700 MHz, CDCl3) δ 7.29 (m, 2H), 6.98 (m, 2H), 6.88 (s, 4H), 3.64 (s, 6H), 2.30 (s, 12H

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• dichlorophosphane 9 from commercially available PCl3 and ethyl vinyl ether using a previously published procedure [68]. Compound 9 reacted with 1 equiv of benzyl alcohol in absolute Et2O and pyridine at −78 °C, followed by quenching of the reaction mixture with H2O. This procedure provided phosphinate 10 in more

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• ), brown solid, yield: 93%. Recrystallisation from hot petroleum ether gave the pure product. 1H NMR (400 MHz, 298 K, CDCl3) δ 7.37 (s, 2H), 2.19 (s, 6H) ppm. 1,2-Dibromo-4,5-bis(bromomethyl)benzene (1c): From 1b: chlorobenzene (4.0 mL) was used as the solvent instead of CH2Cl2 (1 mL). Brown solid, yield

• : 86%. From 1 (two-step, one pot): Brown solid, yield: 82%. Recrystallisation from hot hexane gave the pure product. White solid, 1H NMR (400 MHz, 298 K, CDCl3) δ 7.62 (m, 2H), 4.53 (s, 4H) ppm. 1,3-Bis(bromomethyl)benzene (2a): Petroleum ether (1.5 mL) was used as the solvent instead of CH2Cl2. The

• reaction mixture was kept at 5 °C instead of rt and time was extended by 15% (2 h 20 min for H2O2 dropping and 2 h after the addition). The title product was obtained as pale-yellow solid, yield: 73%. Recrystallisation from hot petroleum ether gave the pure product. White solid, 1H NMR (400 MHz, 298 K

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• solvents were purchased from commercial sources and used without further purification unless otherwise specified. THF, ether, CH2Cl2, and DMF were degassed in 20 L drums and passed through two sequential purification columns (activated alumina; molecular sieves for DMF) under a positive argon atmosphere

• KOH (1.87 g, 33.3 mmol) in water (50 mL). After completion, a yellow precipitate was observed which was filtered and washed with copious amounts of 1 N HCl and diethyl ether. The product 6b was then dried in vacuo to obtain pale yellow amorphous solid (1.15 g, 3.31 mmol, 99%). 1H NMR (500 MHz, DMSO-d6

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• % yield. It is worth noting that the products yielded by these protocols were easily separated as white amorphous solids by concentration and trituration of the obtained residue with diethyl ether. The color of the products indicates that the reactions proceeded without any signs of decomposition

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• of amides from 2-alkynylanilines by using TFBen (benzene-1,3,5-triyl triformate) as a CO source, Pd(OAc)2, DPEPhos (bis[(2-diphenylphosphino)phenyl] ether), and DIPEA (N,N-diisopropylethylamine) in MeCN. After 24 h, Pd(OAc)2 and AlCl3 were added to promote a selective cyclization reaction [14]. The

• the presence of Ni(dme)Cl2 (a nickel(II) chloride ethylene glycol dimethyl ether complex), dtbbpy (4,4-di-tert-butyl-2,2-dipyridyl), Zn(0) and ZnI2 in DMF at 120 °C [42] (Scheme 22). The nickel catalyst catalyzed the oxidative addition and CO insertion on aryl iodide compounds, while the Zn/ZnI2

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• the FPP cyclopropylmethyl analog 51 (Figure 4b) [44]. With FPP ether derivative 52, pentalenene synthase (PenA) and the Δ6-protoilludene synthases (Omp6/7) from Omphalotus olearius several new tetrahydrofurano terpenoids 53–58 were obtained, some of them accompanied with pronounced olfactoric

• synthase (CLS) from Cannabis sativa and 5-epi-aristolochene synthase (TEAS) from Nicotiana tabacum were incubated with 11 synthetic prenyl analogs with ether, thioether, alkyne, or phenyl groups, and six of them (60–65) were converted into several novel monoterpenoids 66–71 [46] (Figure 5). In addition to

• substrates. a) Products of BcBOT2 using iso-FPPs 45–47. b) Biotransformation of 51 by BcBOT2. c) Products of two TSs PenA and Omp6/7 using FPP ether derivative 52. PenA generated compounds 53–57 and 59, whereas Omp6/7 produced 54–59. Biotransformation of noncanonical prenyl analogs 60–65 using two terpene

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• neutral (4ab, 34% yield) and electron-withdrawing (4ac, 27% yield) ones, but no significant changes in the enantiomeric ratio were observed (Scheme 3). Despite the formation of the hemiaminal ether as the major product, the formation of a minor N-Boc pyrrole was also observed as a side-product. To

• products) were found to be somehow unstable when concentrated to dryness during work-up. We hypothesize that a possible cause of such instability might consist in the formation of a highly electrophilic iminium ion upon protonation of the hemiaminal ether by silica or glassware acidity and further

• methanolysis, the hemiaminal ether product 3 is formed. We hypothesize that the enantioselectivity-determining step consists of the migratory insertion of the aryl group bonded to palladium to the pyrroline. The steric effect of the t-Bu group favors the coordination of the pyrroline with the protecting group

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• at 40 °C for 24 h in a sealed vial. Upon completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to give crude products 5a. Further purification was conducted by flash chromatography with 1:6 petroleum ether/EtOAc to afford 5a in 92% yields. The adduct was confirmed

• was purified by flash chromatography with 1:4 ethyl acetate/petroleum ether to afford product 6a. General procedure for the one-pot synthesis of tetrazole-containing 1,2,3,4-tetrahydroisoquinolines 6 A mixture of 2-bromobenzaldehyde 1 (1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl

• (3 mL) was added 10 mol % of Pd(OAc)2, 20 mol % of PPh3, 2 equiv of K2CO3 and the mixture stirred for 3 h at 105 °C under N2 atmosphere. After aqueous work-up, the crude product was purified by flash chromatography with 1:3 ethyl acetate/petroleum ether to afford products 6. General procedure for the

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• mixture of ketone 9e and the O-alkylated enol ether by-product, which was then reduced using NaBH4 to give alcohol 10e with 98:2 selectivity. Similarly, the reaction of 4-methoxybenzyl bromide and 2 gave ketone 9f in 35% yield without chromatography, and when reduced resulted in only a single alcohol

• chiral auxiliary 10a, and following a survey of conditions and isolation protocols, a 90% yield was obtained when 10a was heated in the presence of 2 equivalents of SOCl2 and 5 equivalents of pyridine in DCE. Flash chromatography of the chloroalkyl ether 11a resulted in significant loss due to hydrolysis

• skeletal rearrangement (vide infra). Inclusion of the soft-nucleophile allyltrimethylsilane in the reaction of 10b to trap potential oxocarbenium ion intermediates also resulted in a complex mixture. During the isolation of the chloroalkyl ether products 11a–f, it was apparent that hydrolysis occurred