Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• in the absence of a Brønsted acid additive, the opposite enantiomer 52 was obtained. Mechanistically, an initial kinetic resolution (KR) of (rac)-50 occurs via an Ir-catalyzed asymmetric allylic amination. Due to the higher reactivity of (S)-50, it reacts with 6-hydroxyisoquinoline within 6 minutes

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• describes the enantioselective Michael addition of pyrazoline-5-ones to α,β-unsaturated ketones. The enantioselectivity and chemical efficiency of this transformation were achieved with a cinchona-alkaloid-derived primary-amine–Brønsted acid composite [22]. A good demonstration of how organocatalysis

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• studies by the groups of Akiyama and Terada in 2004 [14][15], many excellent results have been achieved by applying BINOL-derived phosphoric acids, which can act as proton donor and acceptor [16][17][18][19], possessing both Brønsted acid and Lewis base character [20]. Substantial effort has been invested

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

• to NHC-catalyzed reactions. The major part is devoted to chiral Brønsted acid catalysis as it seems so far the most widely used activation principle for the generation of axially chiral compounds. Hydrogen-bond-donating catalysts and various other activation modes complete the discussion of recent

• purities in this process (Scheme 20). Chiral Brønsted acid-catalyzed atroposelective reactions Chiral Brønsted acids became prominent organocatalysts that also promote the syntheses of axially chiral compounds. The amination of aromatic biaryls 65a–g with dibenzylazodicarboxylate catalyzed by

• 219oa (84%, 92% ee). The unique combination of photochemistry and Brønsted acid-catalysis by CPA (R)-C23 was utilized in the cyclization reaction of cinnamates 220 forming N-arylquinolones 221 (Scheme 65) [95]. Optimized reaction conditions led to the formation of products 221 in remarkable yields with

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

• out IEDADA reactions has been a glowing field in recent years [11][12]. In particular, organocatalysis can provide different activation modes to promote enantioselective IEDADA reactions [13][14], based on three strategies (Figure 3): i) LUMO-lowering activation (Brønsted acid catalysis), ii) HOMO

• quinuclidine moiety can act as a base activating a nucleophile, secondly the secondary hydroxy group can participate in hydrogen bonding or can behave as a Brønsted acid (Figure 5). Additionally, the quinoline moiety can interact through π–π stacking with the reactants. On the other hand, the (DHQD)2-based

• Brønsted acid catalysis has been widely studied in asymmetric synthesis [38][39]. While the asymmetric transformations of 2-azadienes have been more intensively investigated, enantioselective derivatizations of 1-azadienes are scarce. In this section, the cycloaddition reactions involving α,β-unsaturated

Synthesis of benzo[f]quinazoline-1,3(2H,4H)-diones

• Ruben Manuel Figueira de Abreu,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2708–2719, doi:10.3762/bjoc.20.228

• and Suzuki–Miyaura cross-coupling reactions followed by Brønsted acid-mediated cycloisomerisation. The developed methodology tolerates various functional groups and leads to moderate up to quantitative yields of the final products. The impact of different functional groups on the optical properties

• . The employment of higher temperatures resulted again in a mixture of 4a and 5a (Table 1, entry 2). Next, p-toluenesulfonic acid (p-TsOH·H2O) was chosen as the Brønsted acid. To our delight, product 5a was obtained in a yield of 59% after 2 hours (Table 1, entry 3). Further investigation showed that

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

• for the resolution of chiral amines [28]. However, it was not until 2004 that they were recognised as efficient chiral Brønsted acid organocatalysts for asymmetric Mannich reactions [29]. Malkov and co-workers revealed [30] that (R)-TRIP can act as a very efficient catalyst for the kinetic resolution

• employing a bulkier allyl-transfer reagent 116. They used a novel pre-formed chiral triborate catalyst 115 in tandem with a non-chiral Brønsted acid and expanded the scope to aliphatic homoallylic amines (Scheme 24). The new method established a scalable, chromatography-free purification protocol for the

• employing chiral Brønsted acid catalyst (S)-TRIP (118) (Scheme 25). In this approach, the racemic β-formyl amide forms the iminium intermediate that undergoes fast equilibration via the enamine tautomer to form preferentially one enantiomer which then undergoes the acid-catalysed aza-Cope rearrangement

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• available in the absence of Lewis acid activation (Scheme 1a) [11][12]. A variety of Lewis acid activators have been reported [13][14][15][16][17][18][19][20][21][22] in an array of group-transfer reactions, including trifluoromethylation, cyanation, and fluorination. Brønsted acid activation has also been

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• Brønsted acid, such as Tf2NH and TfOH, with Bu4NBF4 might be effective to promote the gem-difluorination of alkynes because of the in situ generation of HF equivalents (Figure 1, reaction 6, chemical method). In addition, the electrogenerated acid (EGA) [43][44][45][46][47][48][49][50][51][52] from a

• organic molecules. Herein, we wish to report that the combination of the excess amount of Brønsted acid and Bu4NBF4 or the use of an EGA in Bu4NBF4/CH2Cl2 can serve as suitable reagents for the gem-difluorination of alkynes. These procedures are practical, simple and environmentally friendly, because HF

• ) was reacted with the Brønsted acid (X equiv) and the fluorine source (Y equiv) in the solvent (4 mL) at temperature of T (°C) for Z hours. The chemical yield of the desired product, (5,5-difluorohexyl)benzene (2a), was evaluated for reaction optimization by using the 19F nuclear magnetic resonance

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• subsequent re-esterification was necessary to achieve the desired ketoester. Reduction of the oximes Oximes are commonly reduced to the corresponding amines using either palladium on activated carbon and hydrogen gas [65][66][67][68], or with zinc and a Brønsted acid as source of hydrogen [68][69]. Both

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

• -free conditions. Although some new metal or Brønsted acid catalysts have been reported in the last few years, the main innovations can be found in the use of organic catalysts, enzymes, and compartmentations. A few reports on the in situ generation of reactants and on the reaction conducted under flow

• conditions can also be found. 1.1 Metal and Brønsted acid catalysts As previously mentioned, Sc triflate is the most widely used Lewis acid for the GBB reaction, generally exhibiting higher catalytic activity compared to other metal triflates, such as Yb, In or Bi. No extensive work had been done on rare

• , reported that, by using hexafluoroisopropanol (HFIP) as the solvent, GBB adducts derived from glycal aldehydes could be isolated without additional catalysts in a few hours at 25–50 °C [10]. In this case, however, the role of the solvent as a Brønsted acid cannot be ruled out (this article will be

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

• 10.3762/bjoc.20.136 Abstract The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine–Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent

• presence of one equivalent Brønsted acid additive A5, the catalyst II generates the monoprotonated diamine II-A5. The condensation of the primary amine moiety in II-A5 with the carbonyl group of the α,β-unsaturated ketone 1b in presence of the Brønsted acid leads to the formation of the iminium ion

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

• of anilines through Brønsted acid or transition-metal-promoted conversion of 2-cyclohexanone oximes [15][16][17][18] (Scheme 1, (2)). Moreover, Strauss and co-workers described a green, multicomponent reaction of aromatic aldehydes, 2-cyclohexenone and amines to afford 2-arylmethyl N-substituted

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

• keto function of the hydrazone moiety and the open-chain hemiacetal or aldehyde hydrate in Brønsted acid medium to access 1H-imidazo[5,1-c][1,4]oxazine derivatives (Scheme 1) [21]. Considering that the hydrazone function at C-4 of 4a–r may exist in a tautomeric equilibrium with the corresponding ene

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

• mechanism for the formation of oxamide is shown in Scheme 6. Formation of acetanilide in the reaction of aniline and acetonitrile is known to occur in the presence of Lewis acid catalyst Al2O3 [55]. In our case, either SeO2 (Lewis acid) or H2SeO3 (Brønsted acid) may act as acid catalyst to convert aniline

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• activities. The most direct way of obtaining this nucleus is the Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) between aminopyridines, aldehydes, and isocyanides under both Lewis and Brønsted acid catalysis. However, several catalysts for this reaction have major drawbacks such as being

• conditions and the employment of relatively complex starting materials [19]. A more efficient way of obtaining this nucleus is through the Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) between amidines (aminoazoles), aldehydes, and isocyanides under both Lewis and Brønsted acid catalysis [20

• ][21][22]. Multicomponent reactions (MCRs) provide one-pot reactions, simple synthetic procedures, less waste being produced, fewer purification steps, and a high atom economy [23]. The GBB three-component reaction is carried out in the presence of Lewis or Brønsted acid catalysis to increase the

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• tackle catalyst stability by changing the chloride scavenger [23] or adding other coordinating moieties [24][25]. Hartwig et al. have argued that a Brønsted acid generated in situ from metal triflates may be the “real” catalyst promoting some alkene functionalizations [26]. Therefore, the possibility of

• competing Brønsted acid catalysis in gold-catalyzed alkene functionalization remains a consideration [2], and while it is assumed that alkene activations follow the same prototypical mechanisms as allene and alkyne activations, that is (1) π-activation with nucleophilic attack followed by (2

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• . With this mechanistic blueprint as a backdrop, Phipps and co-workers developed an enantioselective Minisci-type addition, under dual photoredox and chiral Brønsted acid catalysis [44] (Scheme 5A). In their proposed mechanism, the activation of the NHPI ester radical precursor was proposed to occur via

• oxidative quenching photocatalytic cycle employing Ir-based photoreductants and a Brønsted acid additive. While the interaction between the RAE 32 and diphenyl phosphoric acid involves hydrogen bonding, in analogy to the Glorius proposal, it is thought that the substrate activation occurs through proton

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• excellent yield and enantioselectivity. Keywords: asymmetric organocatalysis; chiral Brønsted acid; 3,3-difluoroindoline; Hantzsch ester; transfer hydrogenation; Introduction The introduction of fluoro atoms into organic molecules can alter their lipophilicity, solubility, metabolic stability, and

• organocatalysis using chiral phosphoric acids has also been studied (Scheme 1b) [26][27][28]. In 2010, Magnus Rueping and his co-workers developped an enantioselective Brønsted acid-catalyzed transfer hydrogenation of 3H-indoles [29]. In 2020, Song and Yu successfully applied a new chiral Brønsted acid

• mechanism of the CPA-catalyzed transfer hydrogenation reaction was proposed (Figure 2). The activation of 3,3-difluoro-substituted 3H-indole 1 by protonation through the Brønsted acid generates the iminium A. Subsequent hydrogen transfer from the Hantzsch ester gives the chiral amine 2 and pyridinium salt B

1-Butyl-3-methylimidazolium tetrafluoroborate as suitable solvent for BF₃: the case of alkyne hydration. Chemistry vs electrochemistry

• Marta David,
• Elisa Galli,
• Richard C. D. Brown,
• Marta Feroci,
• Fabrizio Vetica and
• Martina Bortolami

Beilstein J. Org. Chem. 2023, 19, 1966–1981, doi:10.3762/bjoc.19.147

• examples of the hydration reaction of alkynes carried out in ILs. In one case, a dicationic IL, containing sulfuric acid as catalyst, was used as reaction medium to carry out the hydration of different alkynes under mild conditions (40–60 °C, 0.5–1 h) [84]. In a second case, different Brønsted acid ionic

• pseudobenzylic position, as observed in Lewis acid-assisted Brønsted acid (LBA) catalysis [47][48][49][50]. Internal alkynes afforded the corresponding products in good to excellent yields (Table 4, entries 1–3). In particular, the unsymmetrical alkyl(aryl)alkynes 1b and 1c showed a higher reactivity compared to

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• presence of Brønsted acid. In their pioneering research, Tanaka et al. reported the [3 + 2] cycloaddition reactions of trifluoroacetaldehyde hydrazones and glyoxals to give 4-hydroxy-3-trifluoromethylpyrazoles. The resultant pyrazoles containing a free 4-hydroxy group were easily converted to a variety of

• conditions [38] (Scheme 2). Moreover, a chiral Brønsted acid-catalyzed asymmetric 6π electrocyclization of trifluoroacetaldehyde hydrazones for the synthesis of enantiomerically enriched 3-trifluoromethyl-1,4-dihydropyridazines was first developed by Rueping et al. [39]. The strategy involves chiral ion

• pairs and provides a good basis and scope for further extensions and explorations [39] (Scheme 3). Based on the work by Wu et al. and extending their previous work, Rueping and co-workers explored the effects of fluorine in organocatalytic reactions. They developed an asymmetric Brønsted acid–Lewis base

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• and acetic acid (AcOH) as a Brønsted acid, whereas i(a)midation was achieved by using Pd(OAc)2 as catalyst and Cu(OAc)2 as a Lewis acid. A possible mechanism for this chemodivergent C–H activation is depicted in Scheme 16. First, Pd catalyzed the formation of palladacycle I. Oxidative addition of AcOH

• acid organocatalysts were evaluated for sulfenylation on C3, or C2 position of N-heterocycles 115, including indoles, peptides, pyrrole, and 1-methyl-1H-pyrrolo[2,3-b]pyridine. The authors hypothesized a mechanism for the activation of N-sulfanylsuccinimides 1 or 14 by conjugate Lewis base Brønsted

• formation of three-membered cyclic sulfonium ion II followed by ring-opening of sulfonium ion and intramolecular cyclization. The use of a Lewis base/Brønsted acid catalysis system for the sulfenylation of aromatic substrates 4 was reported by Gustafson et al. (Scheme 55) [87]. In the method, catalyst P