Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• on the regioselective electrophilic functionalization of this nitrogen heterocycle [15][16][17][18][19][20][21][22][23][24][25]. However, the vinylogous functionalization of 5-aminopyrazoles has not been described to the best of our knowledge (Figure 2). As a part of our ongoing interest in the

• functionalization of 5-aminopyrazoles [26], we decided to study 4-alkenyl-5-aminopyrazoles as nucleophiles in the vinylogous addition reaction to electrophiles. Herein, we report the regioselective and diastereoselective functionalization of 4-cyclohexenyl-5-aminopyrazoles using alkyl trifluoropyruvates [27][28][29

• yield decreased, possibly due to the formation of imine B, which might be favored by the dehydration effect of the molecular sieves. Conclusion In summary, a regioselective and diastereoselective vinylogous addition reaction of 4-alkenyl-5-aminopyrazoles to alkyl trifluoropyruvate has been studied

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• diaryl λ3-bromanes under remarkably mild conditions with subsequent applications of the in situ-generated arynes in cycloaddition reactions [3], meta-selective reactions with oxygen and nitrogen nucleophiles [4][5], regiodivergent meta or ortho-alkynylations [6], and regioselective (di)halogenation [7

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• groups) with little [73], if any, transition-state binding [36][80][81]. Thus, these macrocycles depend on the catalytic concept of organization; polarization is a minor contributor. Size-exclusion and regioselective outcomes are possible [56][82][83][84][85], and symmetric arrays of chiral units (like

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• sections. Similarly, Pertel and co-workers also demonstrated the use of 2-(2,2,2-trichloroethoxy)-2-oxazoline glycosyl donor 22 (Scheme 4) which could be used for stereo- and regioselective glycosylations using extremely mild conditions [94] and requiring low concentrations of the catalyst. In this case

• the regioselective glycosylation produced products 24:25 in a 4:1 ratio in 61% yield. Aglycon transfer was also observed in the reaction producing 26 in 15% yield. The predominance of product 24 also indicates towards a higher nucleophilicity of the C-4 position of the glucoside acceptor 26

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

• reaction involves an in situ generation of the iminium cation A followed by isomerization to the thermodynamically more stable iminium cation B. Subsequent nucleophilic attack of a copper acetylide enabled regioselective C–C bond formation at the C11 position. After removal of the cyclic acetal, the

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• amidation process of dioxazolones. Dioxazolone 1 binds to the chiral copper complex 3, generating the adduct INT-1. Decarboxylation then occurs, forming the copper nitrenoid intermediate INT-2, subsequently undergoing hydrogen atom transfer in a regioselective manner to afford INT-3. The related acyl

• dioxazolone bearing a linear alkyl group was efficiently converted to the N-vinylamide 26a in good yield. The observed regioselectivity followed the anti-Markovnikov fashion stemming from the regioselective hydrozirconation of the alkyne using Schwartz’s reagent [100]. Aryl substituents on the dioxazolone

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• directly to the alkene, then reacts with the nucleophile to afford product 7. The regioselective 1,2-difunctionalization of allyl alcohol has been developed as a three-component cascade reaction using arenes and sulfonamides as nucleophiles to achieve arylation/hydroamination processes. The reaction

• Biginelli reaction was carried out starting from salicylaldehyde providing hydroxyphenyl-substituted dihydropyrimidines 18 [30]. Subsequently, the regioselective oxidation of the dihydropyrimidine ring in the presence of CAN allowed the formation of new pyrimidinone derivatives 19. The efficacy of Cu(OTf)2

• dihydropyrimidines 18. Regioselective synthesis of 1,4-dihydropyridines 20. Synthesis of tetrahydropyridines 21. Synthesis of furoquinoxalines 22. Synthesis of 2,4-substituted quinolines 23. Synthesis of cyclic ether-fused tetrahydroquinolines 24. Practical route for 1,2-dihydroisoquinolines 25. Synthesis of 2,3

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• of the developed protocol was demonstrated on a gram-scale reaction, where the corresponding product 200 was obtained with an acceptable decrease of yield and enantioselectivity (65%, 94% ee). Mechanistically, a chemo- and regioselective nucleophilic addition followed by dehydration leads to diimine

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• centrifugation. In the same way as a calix[4]pyrrole was used as organocatalyst for cyclic carbonate synthesis from epoxide and CO2, as discussed in section 1.1, Gallo and co-workers investigated the organocatalytic activity of porphyrin/TBACl binary catalytic systems for the regioselective cycloaddition of CO2

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• group from position 4, and then regioselective vicinal functionalization of the generated aryne. The method's compatibility with halide-substituted aryl compounds enhances its versatility and practicality. Moreover, the completion of reaction within a mere 40 minutes at room temperature underscores its

• easily recycled just by washing it with ethanol, retaining its catalytic activity for arylation up to three cycles without any compromise. Thus, this procedure could be considered economic as well as environment-friendly. In 2019, Kalek and co-workers reported the regioselective C–H arylation of 2

• approach providing regioselective access to N2-arylated products along with high yields. The synthetic route could also be applied for the synthesis of N2-arylbenzotriazoles which are promising scaffolds for pharmaceuticals. Subsequently, the impact of the aryl group present in the diaryl iodonium salts on

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

• -galactose and subsequent perbenzoylation afforded an anomeric mixture (α:β = 87:13) of tribenzoyl-4,6-benzylidene-ᴅ-galactose from which the pure α-anomer 10a was separated (Scheme 6) [20]. Cleavage of the acetal and subsequent regioselective replacement of the hydroxy group OH-6 with an iodide by

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

• precise and highly regioselective construction of an array of novel chiral coumarin derivatives, characterized by their exceptional synthetic efficiency and remarkable tolerance towards a broad spectrum of functional groups (Scheme 21, 22a–n). Almost at the same time, Lin et al. [71] also devised a copper

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

• amination: Direct and selective CH-aminations and amidations are challenging reactions. In this context, the regioselective sulfonamidation of (hetero)aromatic groups was achieved by the Lei group via dehydrogenative aryl C–H/N–H cross-coupling [9]. A crucial step in this transformation is the generation of

• method for the regioselective thiolation of aromatic C–H bonds by activating the thiol rather than the arene [19]. For their developed reaction, Pt electrodes were used in an undivided cell with a mixture of HFIP/DCE 3:1 at room temperature under argon. Late-stage functionalization was demonstrated for

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

• . Across all tested substrates, nucleophilic attack predominantly occurred at the homobenzylic position, leading to the regioselective formation of clavam derivative with 2-benzylic substitution due to aryl stabilization of the radical intermediate (see mechanistic discussion below). We briefly

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

• -to-handle reagent, NaOCl·5H2O. Because very little has been disclosed about the reactivity of such 2,3-epoxyesters, their epoxy ring opening by a variety of nucleophiles was carried out and we succeeded in clarifying these chemo- as well as regioselective processes proceeding via the SN2 mechanism to

• failed in this transformation and recovery of 2b was observed (Table 2, entry 10). As was pointed out in the introductory section, the highly regioselective epoxy ring opening is well compared with the case when the nonfluorinated substrate (Ph instead of CF3 in 2b) was employed [25][26]. With 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

• the field of bioconjugation and materials research. We previously reported a regioselective double addition of organic azides to octadehydrodibenzo[12]annulene derivatives with electron-rich alkyloxy substituents. In order to increase the reaction rate, electron-withdrawing substituents were

• introduced into octadehydrodibenzo[12]annulene. In this report, the synthesis of new octadehydrodibenzo[12]annulene derivatives, regioselective double addition of organic azides, and an application to crosslinking polymers are described. Keywords: annulene; click chemistry; polymerization; strain-promoted

• ], and crosslinked polymers [14][15][16][17]. Since crosslinking polymers requires high reaction efficiency under mild conditions, developing such reactions is crucial. We previously reported the regioselective double azide addition to octadehydrodibenzo[12]annulene with hexyloxy substituents (DBA-OHex

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

• , Leishmania amazonensis, Tcruzi epimastigota, Dengue larvicida, and for selected cases Alzheimer and Sars-COVID. For more details, see Table S1 (Supporting Information File 1). Conclusion In summary, we have demonstrated the catalytic regioselective Biginelli synthesis of new S-heterocyclic systems ‒ 4-aryl

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

• base in the Knoevenagel reaction and as a component for ring formation. Cyclization is completely regioselective when arylhydrazines are used; with methylhydrazine, the ratio is greater than 10:1. In addition to malononitrile, derivatives with reduced nucleophilicity (X = CO2R) are also tolerated in

• β-ketoesters to form enaminones 85. The consecutive three-component reaction culminates in cyclization with substituted hydrazines, leading to the regioselective formation of 5-fluoroalkylpyrazoles 83 (Scheme 30) [111]. Following subsequent saponification, pyrazole-4-carboxylic acids can be obtained

• 93 (Scheme 33) [116]. The presence of two equivalents of sodium hydride deprotonates the acidic α-NH of arylhydrazine, thereby determining the regioselective attack in addition–elimination sequence furnishing a hydrazine enaminone intermediate, and ultimately leading to pyrazole 93 after cyclization

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

• Structural Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200 Birmingham, AL, 35244, USA 10.3762/bjoc.20.170 Abstract Herein, we report a pair of regioselective N1- and N2-alkylations of a versatile indazole, methyl 5-bromo-1H-indazole-3

• character of TsO− and triphenylphosphine oxide, precluding any thermodynamic versus kinetic arguments for regioselectivity. Conclusion We have established highly regioselective N1- and N2-alkylations of methyl 5-bromo-1H-indazole-3-carboxylate from diverse commercially available alcohols with excellent

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

• synthesis of 2H-furan-3-ones from mestranol [23]. Initially, a 1,3-dipolar regioselective cycloaddition occurred between the alkyne group of mestranol and an alkanonitrile oxide generated in situ from the corresponding oxime, yielding isoxazoles 31. Later, a reductive ring cleavage of the isoxazole ring was

• decarboxylation of the carboxylic residue when heated at reflux of methanol. After the regioselective cycloadditions, spiro compounds 49a,b were obtained in yields ranging from 75% to 91% (Scheme 15). Related derivatives have similarly been achieved in good to excellent yields [32][33]. Recently, López et al

• as a 17β-HSD3 inhibitor [42]. The same research group reported a new family of 3-spiromorpholinones derived from ADT bearing hydrophobic substituents [43][62]. The synthetic key step involved a regioselective aminolysis of the oxirane 131 with different ʟ- or ᴅ-amino acids (53–99% yields) to obtain

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

• ]. The P450 enzyme BscF is responsible for regioselective abstraction of a hydrogen at C12 and subsequent diastereoselective hydroxylation of the radical intermediate B to produce brassicicene B (10). Meanwhile, further single-electron oxidation of the intermediate B would trigger a Wagner–Meerwein-type

• the chemo-enzymatic approach for synthesizing this family of natural products [57]. Regioselective macrocyclization: tylactone and juvenimicins In the chemical synthesis of macrolides, macrolactone construction most generally involves the generation of activated esters from the corresponding

• (Scheme 7 and Scheme 8) [68]. This chemo-enzymatic total synthesis represents a pioneering approach, as it ingeniously integrates biosynthetic intermediate mimics, synthesized through multiple steps, into the biosynthetic pathway. A cascade of stereoselective carbon chain elongation and regioselective

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

• encoded in the pbt cluster of P. rosea. The thiopeptide GE2270 encoded by pbt undergoes further regioselective modification through C-methylation of thiazoles. The two rSAM MTs PbtM2 and PbtM3 methylate thiazole E and thiazole D, respectively [64]. PbtM2 and PbtM3 show substantial sequence similarities to

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl₂ and NH₄SCN/KSeCN

• Jialiang Wu,
• Haofeng Shi,
• Xuemin Li,
• Jiaxin He,
• Chen Zhang,
• Fengxia Sun and
• Yunfei Du

Beilstein J. Org. Chem. 2024, 20, 1453–1461, doi:10.3762/bjoc.20.128

• efficient method for a smooth selenocyanation of pyrazole compounds. Results and Discussion In our previous work we reported that a regioselective C-5 thiocyanation of the 2-pyridone skeleton could be realized via a PhICl2-mediated electrophilic thiocyanation approach [54]. Inspired by this previous work

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• procedures [16], our consolidated 3-CR strategy [17][18][19] implicates a careful selection of the starting components that ensures the installation of functionalities to be converged, by regioselective control, in different ring-closing processes [20][21]. With these considerations in mind and with the aim

• ), whose sequential acylation process by iso(thio)cyanates 3a–h gives rise to the asymmetric (thio)urea derivatives (intermediate II). The spontaneous nucleophilic attack of the (thio)amide nitrogen on the terminal methyl ester function at C-4 of the starting azo-ene system provides a regioselective