Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• mimics that of 2-benzyl-2,3-dihydrobenzofuran (overlaid in Figure 4), a structural motif that is commonly found within bioactive natural products. Having seen that the conformations of multivicinal fluoroalkanes can be altered by changing the stereochemistry, it follows that other physical properties can

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• 13a,d,e in 71–83% yield (Scheme 4). Carboxylic acid 13a could be reacted with glycine benzyl ester in the presence of HATU and Et3N to form dipeptide 16 (66%). In contrast, N-unprotected 2-aminoprolines are unstable and could not be isolated. Thus, the cleavage of the N-Cbz protecting group in 6b

• ester moiety with LiBH4. In the meantime, the hydrogenolysis of the benzyl ester in dipeptide 16 proceeded smoothly and afforded carboxylic acid 17 in 81% yield (Scheme 4) [16]. Conclusion In summary, the developed electrochemical decarboxylative amidation of readily accessible malonic acid monoesters

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• product 35b was obtained, confirming that the dihaloalkane compound is the source of the methylene unit (Scheme 28c). Depending on the stability of the leaving carbocation, the selectivity of the R–N cleavage follows the decreasing order for the R groups: H, t-Bu, allyl, benzyl > methyl > primary

• amine with two methyl groups and a benzyl or allyl group, the cleavage of the N–CH2Ph and N–allyl bond takes place more selective (by 85% and 67%, respectively), instead of the cleavage of an N–Me bond. This explains the high selectivity observed for some examples in Scheme 27. Finally, this methodology

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• olefins with a wide range of nucleophiles, with many organocatalyzed asymmetric examples highlighted in the literature [23][24]. We have observed that the enantioenriched 1,5-dicarbonyl Michael adducts, synthesized via organocatalyzed reaction of cinnamaldehyde with benzyl phenyl ketone, undergo

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

• triad (red) was hoped to activate the benzyl alcohol nucleophile, but it does not activate (polarize) the electrophile (substrate ester group). (B) One of Rebek’s “clefts” [108][109]. The rigidly organized carboxylic acids both bind the substrate and the transition state for hydrolysis of an acetal. (A

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

• the presence of Pd-C. This deprotection protocol also facilitates an orthogonal deprotection strategy in multistep oligosaccharide syntheses in the presence of benzyl (OBn) groups (Scheme 6). The benzyl and cyanopivaloyl-protected hexarhamnoside derivative 37 was completely deprotected by a single

• -2 position to obtain 1,2-trans glycosides showing orthogonal deprotection according to the need of the compound. They introduced (2-benzyloxyphenyl)acetyl (BnPAc, 43) as a versatile leaving group showing orthogonality to both acetyl and benzyl protecting groups [127]. This group, when placed in the

• of a mixture of 1,2-cis and 1,2-trans glycosides. In this respect ether-type non-participating protecting groups like benzyl (OBn), p-methoxybenzyl (OMBn), and allyl (OAll) are implemented as the temporary protection in the C-2 position in order to obtain 1,2-cis glycoside products. Moreover, the

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• to inhibit p38α MAPK and 0.5 µM for TNF-α [10]. Pyrazolobenzothiazines containing a triazole moiety have also been studied as potential antibacterial drugs [7]. Other applications of N-substituted benzyl/phenyl acetamide pyrazolobenzothiazines include superoxide anion and DPPH radical scavenging

• . Yellow-colored precipitates of product 5 were formed which were separated via filtration followed by washing with excess of water. After drying, recrystallization was done with ethanol. Mp 265–266 °C; yield: 221 mg (88%). Synthesis of pyrazolo-1,2-benzothiazine-N-aryl/benzyl/cyclohexylacetamides 7a–h

• Dried acetonitrile (10 mL) was used to prepare a solution of compound 5 (251 mg, 1.0 mmol) followed by addition of anhydrous K2CO3 (173 mg, 1.25 mmol) under continuous stirring and heating. After 30 minutes, the solution of the respective 2-chloro-N-aryl/benzyl/cyclohexylacetamide 6a–h (1 mmol) in dry

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

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

• reaction was also fruitful to obtain 1,2-dihydroisoquinolines 25 starting from 2-alkynylbenzaldehydes, primary amines and allylic or benzyl bromide, in the presence of zinc and using the combination of Mg(ClO4)2/Cu(OTf)2 as catalyst. The use of a mixture THF/DCE 1:20 as solvent was mandatory, because THF

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

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis

• Remi Peters,
• Levy A. Charleston,
• Karinan van Eck,
• Teun van Berlo and
• Daniela A. Wilson

Beilstein J. Org. Chem. 2025, 21, 47–54, doi:10.3762/bjoc.21.5

• across various applications. In this study, we present a comprehensive methodology for synthesizing, self-assembling, and transforming polysarcosine-poly(benzyl glutamate) block copolymers, resulting in the formation of bowl-shaped vesicles, disks, and stomatocytes. Under ambient conditions, the shape

• broadening their potential applications in drug delivery and nanotechnology. Our findings shed light on the unique capabilities of polysarcosine-based polymers, paving the way for further exploration and harnessing of their distinctive properties in biomedical research. Keywords: biodegradable; poly(benzyl

• functionalities of naturally occurring amino acids, synthetic polypeptides offer a robust platform for designing drug delivery systems that meet the criteria of biodegradability and biocompatibility [13]. The present study focuses on a polysarcosine and poly-ʟ-(benzyl glutamate) block copolymer (PSar-PBLG), as it

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• ), and appetite suppressants (e.g., phentermine) [6]. Phenethylamines can be produced via numerous different procedures [7]. One of the oldest methods involves the reduction of benzyl cyanide with H2 in liquid ammonia with Raney-Nickel catalyst at 130 °C, and high pressure [8]. Another known method is

• ); 13C NMR (151 MHz, D2O) δ 122.41, 124.77, 129.01, 133.06; ESI-MS m/z: [M + 1]+ 171.0; found, 171.1; mp 190–191 °C. Benzyl alcohol (9b): The product formation was monitored by TLC using Hex/EtOAc (6:1). Once cooled to room temperature, the mixture was acidified with 20% HCl solution and extracted with

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• salts [34]. Under these conditions, N-benzyl-4-methylbenzenesulfinamide (6aa) was not observed, and N-benzyl-p-toluenesulfonamide (5aa) was isolated in 29% yield (Table 1, entry 4). To prevent the regeneration of tert-butyl 3-(p-tolylsulfinyl)propanoate (4a) and employ milder conditions, a study was

• primary amine-containing HIRs, or it might be due to the inability of the benzyl moiety to stabilize the sulfenate ion during the reaction. For tert-butyl 3-(p-tolylsulfinyl)propanoate (4a), and similarly to the outcome obtained for BBX 2a, sulfonamides 5ab and 5ac were obtained with moderate yields. The

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

• in moderate yields (42–60%), high diastereoselectivities and good enantioselectivities (68–88% ee) (Scheme 6). The authors also attempted the reaction using N-benzyl-protected 3-chlorooxindole as a substrate. However, in this case, no reaction was observed, which indicated that the N–H group of the 3

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• benzyl azide and triethylgermanyl acetylene (see Supporting Information File 1). The most effective conditions were found to be based on the classical combination of CuSO4/NaAsc, with optimisation (see Supporting Information File 1) delivering the general conditions shown in Scheme 2. These afforded a

• and the starting material could be recovered in each case, consistent with observations by Lam and MacMillan [71][72]. Variation of the steric and electronic parameters of the germanyl acetylene was straightforward (14–17; Scheme 2b). Several limitations were observed (Scheme 2d): benzyl azides

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

• a 4 mmol scale gave dimethyl ester 11a in 99% yield. Unexpectedly, the reaction of branched alcohols with diacyl chloride 2a failed. For example, the reaction with benzyl alcohol resulted in the formation of an overly complex mixture of products. Adding bases to trap HCl did not improve the

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• % yield, however, the related benzyl derived ylides gave 3i and 3j in 73% and 61% yields, respectively. Phenyl esters performed well with this methodology (3k,l), but switching to anilide-derived ylides were consistently poorer performing. The N-phenyl ylide derivative reacted to produce 3m in only 50

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• order to lead to the expected fluorinated tetrahydropyridazines (Figure 4). Results and Discussion First, the difluoro- and trifluoromethylated hydrazones 3a–f were synthesized by condensing the corresponding hydrazide with the fluorinated aldehyde hemiacetal 2a or 2b (Scheme 2). Benzyl and tert-butyl

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• regeneration of 1-fluoro-3,3- dimethylbenziodoxole (12) in 91% yield from isolated benzyl alcohol after the fluorination reaction. A mechanism of the reaction was proposed (Scheme 13) in which the iodane-activated alkene is attacked by fluoride and the aromatic ring, to form a fluorinated phenonium

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

• trifluoromethylthiolated organic peroxides 44 in good yields. Benzyl C(sp3)–H The direct α-functionalization of alkylaromatic compounds 45 with TBHP with the formation of the mixed peroxides 46 was firstly reported by Minisci using Gif conditions – Fe(NO3)3/HOAc/Py (Scheme 19) [61]. Notably, high yields of peroxides 46

• carried out without solvent and at room temperature, using copper(II) acetate as the catalyst. The reaction pathway of tert-butyl perbenzoate synthesis from benzyl nitriles 60 involves the formation of intermediate D. The Kornblum–DeLaMare rearrangement of peroxide D gives benzoyl cyanide E, which is

• further attacked by TBHP to give product 61. Benzyl alcohols 62 were also converted into tert-butyl perbenzoates 63 under the action of the TBAI/TBHP system (Scheme 22) [65][66]. During the process, TBHP oxidizes TBAI into iodine, which reacts with the second TBHP to generate tert-butylperoxy radical B

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

• , see Scheme 1). In order to break the symmetry and to generate the acid function only on one side, benzyl protection was performed. From diols 1, 2, and 3 statistical mixtures of unprotected, mono-, and di-protected products were obtained, from which the isolation of the desired mono-protected products

• bicarbonate (NaHCO₃) provided acids 7, 8, and 9. A byproduct is obtained during oxidation and it is assumed that this is the molecule oxidized at the benzyl position (see Supporting Information File 1, compounds 35–40). Work-up and isolation proved to be difficult, and therefore, the acids were directly

• converted into the methyl esters 10 (54%), 11 (52%), and 12 (46%). The benzyl-protecting group was removed hydrogenolytically to give products 13 (85%), 14 (65%), and 15 (99%). The alcohols were then converted to the triflates 16 (28%), 17 (41%), and 18 (63%). We have chosen 3,4,5-trimethoxybenzaldehyde (19

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• was to be evidenced by a substitution reaction at the alpha position. We started testing the different bases with lithium bis(trimethylsilyl)amide [39]. The reactions did not take place in the presence of LiHMDS (Table 1, entries 1 and 2), using either benzyl bromide or methyl iodide as electrophiles

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

• salt, subsequently leading to decarboxylative C–C coupling. Notably, this method achieves the incorporation of two fluorine atoms in the benzyl position without resorting to hazardous fluorination reagents, transition-metal catalysts, or organometallic compounds. The utility of this reaction is

• benzyl ester generated rather than the corresponding methyl esters. The reaction was also performed with a 6-membered cyclic diaryliodonium salt, which proceeded successfully and produced the respective iodo-containing arylated product in 59% yield with 76% ee after 24 h. Using the same reaction

• of O3-arylated galactosides 64 by reacting benzyl-protected galactoside 63 with diphenyliodonium triflates 16 at room temperature in the presence of potassium tert-butoxide as the base (Scheme 26) [77]. This transition-metal-free approach simplifies the synthesis process. Electron-pushing and

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

• , albeit, in low yield (Scheme 19) [25]. Cleavage of the benzyl groups using boron tribromide afforded β-31a. In contrast to indirubin-N-rhamnoside 17a, its isomer β-31a proved to be rather unstable. This fact was already earlier observed for indigo-N-rhamnoside 5d and again suggests that compounds

• -glycosides Sassatelli et al. reported the synthesis of isoindigo-N-glycosides β-57a–c by reaction of benzyl-protected isatin-N-glycosides β-56a–c with oxindole (55) (Scheme 35) [53][54][55]. Deprotection by BBr3 afforded β-58a–c. Isatins 56 were prepared by glycosylation of indoline, benzylation, and

• oxidation with CrO3. Although this approach allowed for the synthesis of acceptor-substituted isatin-N-glycosides, it proved to be tedious and the yields were low. In a similar way, acetyl-protected isoindigo-N-glycosides were prepared. In addition, benzyl-protected isoindigo-N-glycoside β-58d, containing a

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• ]. In this context, while significant contributions have highlighted the reliable use of diverse organometallic species in the three-component coupling, most examples of sp3-hybridized compounds have remained restricted to allyl [5] or benzyl [5][6] organometallic reagents. Conversely, examples of