Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• of primary amines was reacted with methyl cyanoacetate [46], giving rise to the corresponding cyanoacetamides 1 (Scheme 2). Subsequently, they were reacted accordingly to yield a variety of the targeted precursors, 2-aminothiophenes 2 [42], 2-aminoquinolines 3 [45] and 2-aminoindoles 4 [44], via

• (hetero)aromatic, bulky and linear amines with different substitution patterns. The compounds 2–4 were purified by recrystallization and employed as such (Scheme 2). To our great delight, the heterocycles 2–4 could successfully be subjected to refluxing formamide under neat conditions, instantly yielding

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

• secondary amines via an N-acyl nitrene intermediate [77]. Amidines, found in biologically active compounds, have been widely investigated in medicinal chemistry due to their potent antiviral, antibacterial, anticancer, and other therapeutic properties [78][79][80][81]. As shown in Scheme 4, dioxazolones

• 20 is afforded through protonolysis, regenerating the active copper species to complete the catalytic cycle. 2 Amidation via oxidative insertion to N–O bonds and reductive elimination 2.1 Hydroamidation of vinylarenes Amines bearing stereogenic centers have been widely investigated in the research

• area of medicinal chemistry [93][94][95][96][97]. In 2018, Buchwald and co-workers unveiled the enantioselective synthesis of benzylic amines through the asymmetric Markovnikov hydroamidation of alkenes utilizing diphenylsilane in copper catalysis under mild reaction conditions [98]. Dioxazolones, as

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• asymmetric C(sp3)–H alkynylation of tertiary cyclic amines by merging Cu(II)/TEMPO catalysis with electrochemistry to yield chiral C1-alkynylated tetrahydroisoquinolines (THIQs) (Figure 5) [50]. As a co-catalytic redox mediator, TEMPO plays an essential role in the formation of iminium intermediate 15 and in

• the product are accessible by adjusting the two distinct chiral catalysts. C–N Bond formation In 2018, Mei et al. developed the electrochemical C–H amination of arenes with amine electrophiles using copper catalysis, which provided a step-economical approach for the synthesis of aromatic amines by

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

• reactions conducted step by step. Providing acyclic compounds A three-component Strecker-type condensation of aromatic aldehydes, amines, and cyanides under mild reaction conditions furnishes α-aminonitriles 1 in good to high yields (Scheme 1) [15]. The reaction failed only in the case of acetophenone

• . The Mannich reaction with aromatic aldehydes and cyclic amines was performed efficiently on 2-naphthol, by using SiO2-supported copper triflate under solvent-free conditions, without an additional co-catalyst or additive (Scheme 3) [17]. The treatment of stoichiometric amounts of arylaldehydes

• , secondary aliphatic or aromatic amines and thiols in the presence of catalytic Cu(OTf)2 (1 mol %) in aqueous media was proven to be a sustainable procedure to access thioaminals 5, avoiding high temperatures and/or hazardous reagents required by classical conditions (Scheme 4) [18]. The 1,2

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

• prochiral 2-aryloxyisophthalaldehydes 57a,b with a range of aliphatic and aromatic alcohols 58a–g, as well as heteroaromatic amines 60 (Scheme 19). Chiral diaryl ethers of this type received increased attention lately. Biju, Gao, Zhang, and Zeng groups all reported high degrees of yields and

• amines 76 in the C–H amination reaction with CPA C25, the authors were able to prepare axially chiral para-amination products 78 (Scheme 25) [49]. Such amination products 78 were prepared with high levels of yields and showed remarkable enantiomeric purities. Interestingly, when a phenyl substituent was

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

• is simplified thanks to the ability of 2-propanol to partition from the sodium hydroxide aqueous solution, which allows prompt extraction of the products. Once 2-propanol is evaporated, the products can also be isolated as free amines by dissolving the residue in diethyl ether, decanting it into

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

• have been reported [12]. These reagents have proven effective in delivering azides (I) [13], amides (II) [14], aliphatic cyclic amines (III) [15], phthalimidates (IV) [16], imines (V) [17], sulfoximides (VI) [18], carbazoles (VII) [19], secondary (VIII) [4] and primary (IX) [20] amines (Figure 1). The

• benziodoxolone was generated in situ, via a reaction of chlorobenziodoxolone with sulfinate salts, followed by the addition of amines or hydrazines, respectively. On the follow-up on our research, we envisaged to extend the diversity of BBX reagents as electrophilic amine reagents and investigated their

• formed by carboxylic acids, enhancing its versatility and effectiveness in drug design [27]. Traditional sulfonamide preparation involves combining sulfonyl chlorides and amines [25][28][29]. Despite the efficiency of traditional methods, challenges still remain, e.g., use of harsh conditions, like

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

• , they can be attacked by a nucleophile and undergo a 1,2-addition or conjugate addition leading to the production of allylic amines or aliphatic imines, respectively. They can also behave as C4 synthons in cycloaddition reactions such as the aza-Diels–Alder reaction, giving access to nitrogen-containing

• covered in this review are hydrogen-bond donors such as thioureas and squaramides, Brønsted bases such as tertiary amines, and Brønsted acids such as chiral phosphoric acids. As depicted in Figure 4, a bifunctional squaramide is able to activate both an α,β-unsaturated imine through hydrogen bonding with

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• –activity relationship data, leading to speculation over the moieties responsible for their antibiotic effects. A reduction in the number of amines in the polymeric chain and the absence of a primary amine was noted to decrease bioactivity by Xu et al. [7]. Research reported by Khan et al. in 2014 [9] also

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

• from isoxazole 1a and primary and secondary amines according to the conditions described in entries 9 and 10 in Table 2, with yields of up to 78% (Scheme 4). An experiment with benzylamine and isoxazole 1a on a 1.5 mmol scale gave diamide 10a in 84% yield. The structure of compound 10h was confirmed by

• -2,2-dicarboxamides were prepared using primary and secondary amines in 53–84% yield, and the reaction is scalable. Methyl and ethyl esters of 3-phenyl-2H-azirine-2,2-dicarboxylic acid were prepared in 76–99% yield from 3-phenyl-2H-azirine-2,2-dicarbonyl dichloride and methanol or ethanol, but the

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

• obtain α-acylaminoamides. Innovation in recent years with alternative reagents, like N-hydroxyimides or nitric acid in place of an acid, N-alkylated hydrazines, or nitrobenzene derivatives (reduced in situ to anilines) instead of amines, and in situ-prepared isocyanides, makes it a versatile method for

• heterocyclic scaffold is subsequently formed [58]. In 2015, Xu et al. [59] reported the synthesis of 1,5-benzodiazepines using the UDC approach. The process begins with Ugi-4CRs, incorporating amines, glyoxaldehydes, 2-(N-Boc-amino)phenylisocyanide, and carboxylic acids. Following this, the Boc group is

• substituted 1,4-benzodiazepin-3-ones using the UDC method. This process involves N-Fmoc-amino acids, isocyanides, amines, and derivatives of 2-fluorobenzaldehyde (Scheme 15). Ugi-4CR/reduction/cyclization (URC) strategy: The URC pathway enables the synthesis of benzodiazepines by using amine surrogates, such

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

• fluoride and BF3·OEt2 as activator. A range of unsaturated amines 5 were cyclised to racemic β-fluorinated piperidines 6. Good yields were reported for all compounds except those with substituents present on the alkene. Homologation of the carbon chain from 5 to 6 carbons gave both 6- and 7-membered rings

• , intramolecular aminofluorination of a range of unsaturated amines formed β-fluorinated piperidines 6 and 3-fluoroazepanes 7 in good yields. Again, yields only significantly fell with substrates containing substituents on the alkene. Depending on the length of the alkyl chain, both 6- and 7-membered rings were

• the product. Li reported a haloamination of unsaturated amines in 2014 (Scheme 5) [30], to form fluorinated piperidines 6 using PhI(OAc)2 as an oxidant and BF3·OEt2 as the source of fluoride. Fluorocyclisations gave lower yields compared to other halocyclisations reported by the authors

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

• various amines tested, only the secondary amines (morpholine) led to product formation, confirming the formation of enamine in the catalytic cycle. The proposed mechanism suggested that the amine, photocatalyst, and light each played crucial roles (Figure 14). The porphyrin acted as both a photoredox unit

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

• with radical B to form product 73. The mechanism of the transition metal-catalyzed oxidation of amines with TBHP was studied in detail in the work of Doyle and Ratnikov [71]. The scope of the amines 74 that can be functionalized by the tert-butylperoxy fragment was significantly broadened by using a

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

• this Li and Jiang, created an effective ball-milling process for the N-arylation of amines 38 with the assistance of diaryliodonium salts 16 (Scheme 15) [67]. The arylation of an amino group or nitrogen heterocycle occurred effectively when the reaction is performed under solvent-free conditions or

• additives. An efficient conversion was detected when the substrate contains electron-rich functionalities. In contrast, the yield dropped notably when the amines were substituted with electron-deficient functionalities. In addition, asymmetric diaryliodonium salts were examined, and the transfer of the aryl

• group with a less hindered portion is observed. The mechanism revealed the reaction undergoes the homolytic cleavage of the diaryliodonium salt to produce an iodoaryl radical cation, which further reacts with the amine to acquire the corresponding diaryl amines. Moreover, a similar reaction tried with 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

• stoichiometric amount of LiCl was essential for the efficiency of the subsequent three-component coupling with aldehydes and amines. A variety of primary, secondary, and tertiary organozinc reagents as well as secondary amines and aromatic aldehydes could be used for the straightforward preparation of α-branched

• amines. Interestingly, whereas previously reported work describing the preparation and reaction of organozinc iodides in acetonitrile showed higher reactivity of secondary organozinc reagents over primary ones, reactions in THF in the presence of LiCl led to opposite results, with higher reactivity of

• primary organozinc reagents. Keywords: alkyl bromides; branched amines; Mannich reaction; multicomponent reaction; zinc; Introduction The multicomponent Mannich reaction is one of the most powerful tools available in organic synthesis for the straightforward generation of α-branched amines [1][2][3

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• diastereomers 12 and 13 are often easily separable, and each diastereomer of optically active alcohols or amines can be obtained with an excellent optical purity (reactions 3 and 4 in Scheme 1). To the best of our knowledge, these are the only four works for the preparation of optically active substances having

• fluoroalkylated amines 15 with high optical purity could be easily prepared through [1,3]-proton shift reactions of optically active imines 14 which in turn were readily synthesized by condensation of various perfluoroalkyl ketones with optically active (R)-1-phenylethylamine (Scheme 2a) [25][26][27][28][29][30

• ][31][32]. Therefore, we envisioned that optically active tetrafluoroethylenated amines 17 could be synthesized by applying the [1,3]-proton shift to optically active imines 16 derived from readily prepared tetrafluoroethylenated ketones (Scheme 2b). In this paper, we describe the details of the [1,3

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

• :1 (Scheme 3, 3e). Carbonates with aryl or styryl residue can undergo the reaction smoothly (Scheme 3, 3f–k), but alkyl-substituted substrates showed low yields (Scheme 3, 3l and 3m). Moreover, secondary amines with various substituents, acyclic amines, primary amines, or even the amine moieties in

• et al. [63][64] reported the first amine-mediated highly enantioselective copper-catalyzed asymmetric yne-allylic substitution, affording 1,4-enynes with up to 98% ee and >20:1 rr. A series of secondary amines can react smoothly and achieve good enantioselectivities and regioselectivities (Scheme 7

• and yne-allylic substitution. Challenges in achieving highly selective yne-allylic substitution. Yne-allylic substitutions using indoles and pyroles. Yne-allylic substitutions using amines. Yne-allylic substitution using 1,3-dicarbonyls. Postulated mechanism via copper acetylide-bonded allylic cation

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• indole alkaloids. Here, we develop a novel approach for the one-pot multistep synthesis of different spiro[indole-isoquinolines]. The protocol proposed involves the visible light mediated oxidation of N-aryl tertiary amines using bromochloroform with the generation of a reactive iminium species, which

• efficient methods for the synthesis of heterocycles by multicomponent processes and domino reactions [16][17][18][19][20], here we disclosed the oxidative one-pot four-step synthesis of 2-amino-3,3’-spiroindolenines using readily available tertiary amines, electron-rich anilines and isocyanides as starting

The scent gland composition of the Mangshan pit viper, Protobothrops mangshanensis

• Jonas Holste,
• Paul Weldon,
• Donald Boyer and
• Stefan Schulz

Beilstein J. Org. Chem. 2024, 20, 2644–2654, doi:10.3762/bjoc.20.222

• , including piperidone [10], amines [5][10], and amides [3][5][10] have been also observed in certain species. The analyses of SGS in vipers (Viperidae) focused on New World pit vipers (Crotalinae). Early analyses of SGS lipids by thin-layer chromatography (TLC) [14], indicated that two pit vipers, the Timber

Efficient modification of peroxydisulfate oxidation reactions of nitrogen-containing heterocycles 6-methyluracil and pyridine

• Alfiya R. Gimadieva,
• Yuliya Z. Khazimullina,
• Aigiza A. Gilimkhanova and
• Akhat G. Mustafin

Beilstein J. Org. Chem. 2024, 20, 2599–2607, doi:10.3762/bjoc.20.219

• : oxidation; 6-methyluracil; peroxydisulfate; phthalocyanine catalysts; pyridine; Introduction The Elbs and Boyland–Sims peroxydisulfate oxidation reactions offer a convenient means of introducing the hydroxy function into phenols and aromatic amines [1]. The oxidation of phenol using peroxydisulfate was

• first demonstrated by Karl Elbs in 1893 [2], with E. Boyland later expanding this reaction to include aromatic amines [3]. Concurrently, the successful oxidation of several pyrimidine derivatives was also reported [4]. Since then, the reaction has been extensively researched on various classes of

• reactions was made. It has been suggested that a nucleophilic substitution of the peroxide oxygen atom occurs in peroxydisulfate [32]. Regarding phenols (Elbs reaction), there is also a nucleophilic substitution of the phenolate ion. For aromatic amines (Boyland–Sims reaction), a neutral nitrogen atom of

Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

• Battini Veeraiah,
• Kishore Ramineni,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Hélène Solhi,
• Rémy Le Guevel,
• Chada Raji Reddy,
• Frédéric Justaud and
• René Grée

Beilstein J. Org. Chem. 2024, 20, 2592–2598, doi:10.3762/bjoc.20.218

• this paper, we report a short and efficient synthesis of novel N-arylbenzo[h]quinazoline-2-amines. We have prepared a focused library of nineteen representative examples which have been submitted to cytotoxicity assays against a representative panel of eight cancer cell lines and several molecules gave

• scaffolds for bioactive molecules. Thus, it appeared interesting to explore novel molecules with extended aromatic units around this basic quinazoline core and our first choice was N-arylbenzo[h]quinazoline-2-amines with the general structure C as indicated in Figure 1. Very limited studies have been

• -amines and it was exemplified through the preparation of a focused chemical library with 19 members. In addition, the cytotoxicity assays afforded interesting results demonstrating that the substitution on the anilino part can have significant effects on their bioactivity. Two molecules (4a and 4i

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids

• Andrey N. Komogortsev,
• Constantine V. Milyutin and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 2585–2591, doi:10.3762/bjoc.20.217

• only in the presence of a strong base (DBU). Results and Discussion The starting allomaltols 3 bearing an amide fragment in the side chain were prepared by reaction of dihydropyranones 5 with appropriate amines 6 applying the previously described method [33][34] (Scheme 2). At first, amide 3a was

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

• , which reported the merger of electrochemistry and bioconjugation in 2018 (Scheme 4b) [11]. In 2020, Zheng and coworkers developed an interesting iodoamination of indoles using unactivated amines and benzotriazoles [12]. This difunctionalization reaction was carried out in an undivided cell with an RVC

• protocol for the installation of sulfonamide groups using commercially available SO2 and amines (Scheme 12) [20]. This method is highly appealing for industrial applications and LSF. The proposed mechanism begins with the anodic oxidation of the arene substrate. The resulting radical cation intermediate is

• was demonstrated by the LSF of primary natural and pharmaceutical amines carrying potential competing nucleophiles, such as tryptamine and primaquine (Scheme 16). In the context of electrochemical difunctionalizations the Lei group published a transition-metal-free electrochemical difunctionalization

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

• shorter period possibly because of its significantly high electrophilicity by the attachment of three strongly electron-withdrawing moieties. Reactions of (E)-3-Rf-2,3-epoxypropanoates 2 with amines, thiols, and metal halides Because the epoxide ring opening is known to occur in an SN2 fashion, compounds

• 2 were recognized as versatile building blocks for the construction of 2-amino-3-hydroxypropanoates with 2,3-anti stereochemistry, if appropriate amines work nicely in a nucleophilic manner [44]. After the brief optimization of the conditions for the reaction of 2b and p-anisidine, good yields with

• high stereoselectivity were similarly recorded for the other substrates 2c and 2d possessing different Rf groups at the 3 position (Table 2, entries 1–3). Mixing of 2b with different primary (entries 4–7 in Table 2) and secondary (entries 8 and 9) amines led to the formation of the respective products