Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• structure of 16 was confirmed by serial X-ray crystallography using an X-ray free-electron laser (XFEL) [deposition number CCDC 2352718) [54][55]. We then performed a Strecker-type reaction on the aldehyde 16 to construct an α-aminonitrile 17. To our delight, the key intermediate, 2,3-diaminobenzofuran 11

• measurements (Figures S20 to S25, Supporting Information File 1). A notable feature of this cascade process is the temporary protection of the C≡N triple bond, nitrile in the key intermediate 11, by the 2,3-diaminobenzofuran group. This facilitates the site-selective activation of the alkyne triple bond by the

• –Spengler-type reactions. (c) This work: streamlined modular assembly featuring copper(I)-catalyzed regiocontrolled three-component coupling (8 → 10), one-pot formation of the 2,3-diaminobenzofuran ring in the key intermediate 11, and subsequent gold(I)-mediated regiocontrolled 6-endo hydroamination

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• was achieved in 5 steps starting from commercially available 2-bromo-4-fluoro-1-nitrobenzene (1, Scheme 1 and Scheme 2). For the preparation of the key intermediate 5 (Scheme 1), self-coupling of 1 in the presence of copper followed by reduction of the nitro group generated diamine compound 3 (89

• room temperature. (a) PL spectra of the PhFlOP-based emitters 7 measured in toluene at room temperature. (b) PL spectra of 7-H measured in different solvents at room temperature. Preparation of key intermediate 5. Synthesis of PhFlOP-based molecules 7. Crystal data and structural parameters for 7-H

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• was withdrawn from phase III clinical trials due to insufficient efficacy compared to current antipsychotic drugs (APDs). However, POM demonstrated to be effective to treat certain populations [69]. The large-scale synthesis of a key intermediate of POM was described by Waser et al. [70] in 2011. In

• /cyclization approach. General synthesis of 2,3-dichlorophenylpiperazine-derived compounds by the Ugi reaction and Ugi/deprotection/cyclization approach. Bucherer–Bergs multicomponent reaction to obtain a key intermediate in the synthesis of pomaglumetad methionil (POM). Ugi reaction to synthesize racetam

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

• )] [40]. Introduction of the tert-butylperoxy fragment into the allylic position of substituted cyclohexenes 6 was carried out using Pd(OAc)2 in ambient conditions (Scheme 5) [41]. The corresponding allylic peroxy ethers 7 were synthesized in 62–75% yields, the key intermediate was proposed to be L2Pd(OO

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• acetylide-bonded allylic cation as the key intermediate is proposed (Scheme 6a). It is worth noting that the nucleophilic attack favors a less sterically hindered site. Therefore, disubstituted alkene moiety prefers γ-attack while trisubstituted alkene moiety is inclined to α-attack (Scheme 6b). Lin and He

• vinyl allenylidene is the key intermediate during the process (Scheme 14). Recently, Fang et al. [67] used electron-rich arenes as the nucleophiles to achieve remote enantioselective control of yne-allylic substitutions. It is worth noting that when indoles or indolizines were used, the reactions

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

• from the commercially available β-lactam 9, a key intermediate for the industrial preparation of carbapenems. Starting from the reaction conditions reported by Nicewicz and Morse [28], we optimized the conditions with compound 8c as the model substrate for the photoredox cyclization (Table 1). The

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

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

• concerted SN2-key intermediate 60 must be at least 18.9 kcal/mol more favoured than a separated imine–chloride ion pair 61 attacked by the free allylsilane (Figure 3). Altogether, the developed methodology can be formally viewed as a useful tool for the enantioselective synthesis of chiral α-carboxyl-2,3

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 radical species to the isocyano group of 29 to form the imidoyl radical 30 as a key intermediate, which adds intramolecularly to the ortho-aryl group. The subsequent aromatization with the release of hydrogen (or proton) affords 31 in good yields. Nanni et al. reported the reaction of 2

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

• of these compounds against various diseases. Review Spiro steroids with four-membered heterocycles Spirooxetane steroids In 2003 Wüst et al. reported the synthesis of the oxetan-3-one derivative 2 in an overall yield of 4.2% from hydrocortisone, in six steps. A key intermediate for oxetan-3-one 2 was

• -toluenesulfonic acid-mediated hydrolysis led to the cyclization reaction yielding the steroidal 17-spiro derivatives. The procedure was applied to synthesize drospirenone (Figure 1) and extended to build the spirolactone 23 from DHEA, a key intermediate toward the popular diuretic spironolactone (Scheme 7). 17

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• -cubanes (Scheme 9B) [51]. Partial deprotection of diester 88 led to acid 89 as a key intermediate and in situ activation of the acid as the hypervalent iodine complex enabled a photoredox decarboxylative amination to 1,2-cubane 90. Alternatively, conversion of the acid moiety of 89 to redox active esters

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• synthetic intermediate of 2 to spiroviolene. By taking advantage of the DFT transition state analysis of the hydroboration reaction of a key intermediate, as well as NOE correlation analysis of the resultant product, Snyder and co-workers have reassigned the right structure of spiroviolene to 1. However

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• pathway, the bergamotene sesquiterpenoid (I) is presumed to be a key intermediate cyclized from farnesyl diphosphate (FPP) via nerolidyl diphosphate (NPP) followed by a bisabolyl cation [14]. Subsequent oxidation (bishydroxylation) catalyzed by some oxygenase such as P450 would afford the key intermediate

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• diverse dibenzodiazepinones via a copper-catalyzed C–N bond coupling between 2-halobenzoates and o-phenylenediamines leading to a key intermediate that undergoes an intramolecular N-acylation to afford the corresponding dibenzodiazepinone structure in high yields (Scheme 1b) [14]. Another innovative

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• EtOH, and NaOH in water (Scheme 1). The key intermediate of the macrocycle preparation, imidate 4, was synthesized using the reported procedure [43] by refluxing a solution of aminopyrazole 3 in triethyl orthoformate. First, we studied the reaction of imidate 4 with hydrazine hydrate in EtOH under

• )) for the N2H4-promoted transformation of pyrazolopyrimidine (E)-8 into macrocycle 5 in MeOH solution. Free energies in kcal/mol at 298 K and 1 atm. Synthesis of the key intermediate of the macrocycle preparation, 3-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carbonitrile (4). Synthesis of

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• shown in Figure 14. 2-Methylbut-3-en-2-ol (14.1) was used as substrate and the next steps were almost comparable to those reported in Figure 13. The key intermediate 14.4 was isolated after a three-step sequence and used to prepare 14.5. 1.3 Analogues of PAF with modification at the sn-2 position The

• 22.10. However, the last step features the lower yield (54%) of this 8-step synthesis. In 1994, Bittman et al. reported an alternative strategy to introduce the phosphocholine moiety by the preparation of a cyclic phosphite as a key intermediate [119]. This one-pot three-step sequence starts with the

• alcohol with iodoethane and the transformation of the t-Bu ether in acetyl ester following the method of Ganem and Small [141], produced, after saponification, the key intermediate 31.6. In 1993, Pinchuk reported a stereocontrolled synthesis of both enantiomers of analogues of edelfosine featuring a C18:1

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• oxidative alkylation of cyclic benzyl ethers with malonates or ketones. Oxygen is used as a terminal oxidant at atmospheric pressure. The key intermediate of this oxidative coupling reaction is benzyl alcohol intermediate C (Scheme 4) [52]. The generation of N–O radicals from NHPI in the presence of oxygen

• metal-triggered oxidation of the ether substrate to obtain the corresponding radical or oxonium ion as the key intermediate to obtain the final coupling product. Subsequently, some novel Co-catalyzed coupling mechanisms have been proposed. In 2016, Lu et al. reported that the Co/TBHP catalyst oxidation

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction

• Ziying Xiao,
• Fengshun Xu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1234–1242, doi:10.3762/bjoc.19.91

• ), in which the in situ-generated adduct of thiophenol and 3-phenacylideneoxindole was believed to be the key intermediate [53][54][55]. Inspired by these elegant synthetic protocols and in continuation of our aim to develop convenient reactions for the synthesis of diverse spiro compounds [56][57][58

Unravelling a trichloroacetic acid-catalyzed cascade access to benzo[f]chromeno[2,3-h]quinoxalinoporphyrins

• Chandra Sekhar Tekuri,
• Pargat Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2023, 19, 1216–1224, doi:10.3762/bjoc.19.89

• with 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and dimedone in the presence of 20 mol % trichloroacetic acid in chloroform at 65 °C. Interestingly, a sequential approach for constructing copper(II) benzo[f]chromeno[2,3-h]quinoxalinoporphyrin 3 was also followed by capturing a key intermediate

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• beyond the frontier orbitals of the neutral photocatalyst and thus, higher redox potentials. However, the identity of the key intermediate has remained a matter of debate [40][70][71]. Full elucidations of the mechanism toward confirming the key(/main) active catalyst species and possible deactivation

• transfer. Second-order kinetics analyses revealed that rapid charge recombination (e.g., kCR (PC1•−) = 2.6 × 108 M−1 s−1) is a significant deactivation pathway in the generation of the key intermediate. This deactivation by back electron transfer taking place in the Marcus-inverted region of electron

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• -substituted indoles which effectively attacked the electrophile through the C2 position. The reaction was even compatible with pyrroles (Scheme 7a). The utility of this methodology was successfully demonstrated by the synthesis of product 23a, the key intermediate of natural product (+)-trigonoliimine (Scheme

• was shown by synthesizing 110, a key intermediate of (R)-bifonazole (Scheme 25b) [55]. Thioureas and squaramides In 2018, Yang, Deng and co-workers developed an aza-Friedel–Crafts aminoalkylation of 4- and 5-hydroxyindoles 111. As electron-demanding component, N-Boc pyrazolinone ketimines 100 were

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• ][79][80][81][82][83][84][85]. To test this concept, we turned our attention to the synthesis of key intermediate 5 (Scheme 1). The synthesis began with protection of the indole nitrogen of the known compound 1, which is readily available from commercially available 4-bromoindole in one step [62

• ]. Regioselective palladium-catalyzed prenylation of 2 with prenylboronic acid pinacol ester and subsequent hydrolysis with LiOH provided the linear prenylated acid 4 in good yield. Coupling acid 4 with N-hydroxyphthalimide using DCC and a catalytic amount of DMAP afforded the key intermediate 5 in 59% yield. With

• functionalized 3,4-fused tricyclic indoles with medium-sized rings (seven and eight), which have been largely neglected in previous studies, can be synthesized by this new protocol. Notably, the reaction has been successfully applied in the formal synthesis of (±)-6,7-secoagroclavine, a key intermediate for a

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• persulfate (K2S2O8) as the exclusive reagent [14]. The mechanistic study revealed that an initial oxidation to an iminium ion could be the key intermediate in the intramolecular cyclization step. In sharp contrast, when N-aryl(benzyl)amines that do not have an ortho-substituted nucleophile in aniline ring

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• isolated, further confirming the involvement of a malonyl radical generated by the cleavage of the C–Br bond of 2a [28]. Next, an attempt was made to identify the key intermediate of the reaction (Scheme 3B). When compound 5 was subjected to the acetylation reaction individually with Zn(OAc)2 and AcOH