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

• limited to methanol due to solubility problems, and HClO4 was selected because other Brønsted acids caused amine deprotection. The GBB adducts 58 could be further elaborated through a Buchwald intramolecular nucleophilic substitution/cyclization, as it will be described in section 3.3. 3 Novel scaffolds

• -substituted products 60 underwent TFA-promoted deprotection which triggered the intramolecular cyclization to furnish the indole moiety in the desired products 61. A control experiment showed that the GBB product 60 was obtained as the sole product in the absence of acid catalyst. Another group developed the

• same reaction via a two-step synthesis [58]. Initially, the three starting materials were subjected to the GBB reaction in the presence of a catalytic amount of ZnCl2 to give the fused products 60. Then, the cyclization was carried out using TFA to deliver 61 (14 examples) in yields ranging from 60% to

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• significant topic. Surprisingly, there has been limited information on 5-deazaalloxazines (dAll) synthesis [20][21][22]. Most known methods employ the cyclization of 6-(arylamino)uracils with one-carbon reagents such as triethyl orthoformate, dimethylformamide dimethylacetal, carbon disulfide, N,N

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• times dehydrated was identified. Cyclization reactions introduced thioether cross-links between dehydrated Thr/Ser residues and specific cysteine thiol groups. However, due to identical masses of dehydrated linear peptides (lacking thioether rings) and cyclic forms (containing Dhb and Dha rings), a

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• component, after the formation of the expected Ugi bisamide products, subsequent post-transformations allow the synthesis of products of intramolecular cyclization [19][20][21][22] and/or products of a tandem combination of several reactions (Scheme 1) [22][23][24][25][26]. At the same time, the use of so

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• [11]. Different strategies have been developed to avoid these competitive reactions, the most common ones being the use of protecting groups (Ugi/deprotection/cyclization strategy) [12][13][14] or of surrogates of amines [15]. However, direct incorporation of the second amine without derivatization is

• with a reduced reactivity in the synthesis of 3H-benzo[e][1,4]diazepin-5-ones, heterocycles previously synthesized by our research group through Ugi/Staudinger/aza-Wittig and Ugi/reduction/cyclization sequences, using 2-azidobenzoic [20] and 2-nitrobenzoic [21] acids, respectively. The first

• workup the only product observed was the corresponding benzodiazepinone 5, resulting from a spontaneous cyclization of the Ugi adduct, in a six-center four-component Ugi reaction (U-6C-4CR), which prevents the need of additional steps (Scheme 1, Table 1). Due to the interest of these results and

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

• protecting group yielded the corresponding hydroxyalkynyl derivative 4. Subsequent Lindlar reduction resulted in the (Z)-alkene and a chemoselective tosylation of the primary alcohol led to the formation of tosylate 5. This intermediate underwent a stereospecific 4-exo cyclization upon exposure to iodine

• reported the formation of an α,α-dicyanoalkene from dehydroepiandrosterone (DHEA) and its efficient transformation to dienamides 15 in a single step via a cascade reaction [15][16]. The construction of the β-lactam ring involved a cascade 4-endo N-cyclization/aerobic oxidation sequence in presence of

• sodium hydride, yielding moderate yields (ranging from 23% to 68%). The cyclization initially formed the non-isolated intermediate i, which was oxidized by molecular oxygen from air, introducing the hydroxy group at the α-position of the cyano group. The protocol utilised mild conditions and short

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

• well as their analogs, is outlined with an emphasis on comparing these chemo-enzymatic syntheses with the corresponding natural biosynthetic pathways. Keywords: chemo-enzymatic synthesis; late-stage modification; reactive biosynthetic intermediate; regio- and stereoselective (macro)cyclization; total

• stereoselective cyclization reactions. This review aims to provide an overview of these approaches and parallel comparisons with original biosynthetic pathways by highlighting five examples of chemo-enzymatic total syntheses of natural products reported since 2017. The examples are the synthesis of cotylenol (1

• , and subsequent reduction of the exomethylene at C11–C18 catalyzed by BscH yield brassicicene O (12). Renata and co-workers successfully accomplished the chemoenzymatic total syntheses of cotylenol (1) and nine brassicicenes (Scheme 3) [19]. In the cyclization phase, a suitably functionalized 5/8/5

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• . Key to the successful development of this two-step process is the identification of a benzhydryl-protecting group, which orchestrates the photochemical Norrish–Yang cyclization and facilitates the subsequent ring opening. Keywords: azetidine; Norrish–Yang cyclization; ring-opening reaction; ring

• , endergonic transformations can be realized [3]. A promising strategy for the synthesis of complex products lies in the combination of photochemical cyclization and strain-release reaction (Scheme 1a) [4]. In this ‘build and release approach’, a simple precursor is cyclized upon irradiation. Subsequently, a

• by Norrish–Yang cyclization, which employs easily accessible α-aminoacetophenones as starting materials [11][12][13][14][15]. Furthermore, ring-opening reactions of azetidines have been recently achieved using sulfur and oxygen nucleophiles [16][17][18][19][20][21][22][23][24][25]. However, methods

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• . arabica, and Coffea eugenioides (Eugenioides coffee plant) all contained >30 unique transcripts for potential precursor peptides. The core sequences themselves were typically 4 or 5 amino acids in length and most often contained a tyrosine for cyclization. However, a few sequences appeared to have a

• tryptophan at the position for cyclization, indicating they may correspond to the stephanotic acid-type burpitides like moroidin (Trp-indole-C to carbon crosslink, Figure 3) [4]. Amaranthaceae family The Amaranthaceae family is home to the known moroidin producer, Celosia argentea var. cristata (Cockscomb

Predicting bond dissociation energies of cyclic hypervalent halogen reagents using DFT calculations and graph attention network model

• Yingbo Shao,
• Zhiyuan Ren,
• Zhihui Han,
• Li Chen,
• Yao Li and
• Xiao-Song Xue

Beilstein J. Org. Chem. 2024, 20, 1444–1452, doi:10.3762/bjoc.20.127

• ][22], unsaturated alkane addition [23][24], and cyclization [25][26]. Despite the rapid development of hypervalent iodine(III) reagents, the exploration of isoelectronic hypervalent bromine(III) and chlorine(III) reagents has been comparatively limited despite their demonstrated potential for unique

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

• heteroring closure, positioning appropriate functions both at N-3 and C-4 of the (thio)hydantoin frameworks 4a–r (30–81%) broadening their usable decorations (Scheme 2). Recently, we reported that compounds 4a, 4f, and 4m undergo an intramolecular cyclization process through the involvement of the restored

• -hydrazino form [17][24][25], we conceived the idea of reversing the reactivity of 4a–r in the six-membered cyclization process (N- vs O-annulation) through the generation of an electrophilic oxocarbenium [26][27] cation intermediate from the acetal residue at N-3 of the (thio)hydantoin core. To pursue our

• (entries 1–7, Table 1). Similarly to what was observed by Yu and co-workers for the intramolecular cyclization of alkynyl aldehyde acetals [28][29], it was found that the use of FeCl3 provided the better result in terms of overall yield (entry 3, Table 1). Moreover, the choice of iron(III) seemed to have

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• position and subsequent cyclization will furnish the desired oxazoline. Conclusion We have developed a hypervalent iodine-catalyzed amide and alkene coupling reaction. This reaction protocol furnished useful oxazoline products and introduced the use of lithium salts to activate hypervalent iodine catalysts

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• , presumably due to the increased stability of isomer 18 towards acids. This corresponds with the results for the previously reported triazene cleavage to diazonium intermediates and subsequent cyclization to triazine derivatives [3]. In the next step, the obtained pyrazolyl azides were reacted with different

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• organic dye Mes–Acr–MeClO4 as photocatalyst (Scheme 5). They demonstrated intermolecular radical cyclization of o-hydroxybenzoic acid derivatives with terminal alkynes to afford flavone derivatives. Here, functionally diverse flavonoids were synthesized in moderate to excellent yield by reacting various

• iodide leads to the formation of 23, which further undergoes 5-endo-trig cyclization, followed by fragmentation to produce an alkyl radical and a cyclic thiocarbonate 25. These alkyl radicals then interact with B2cat2 (19) to produce a variety of structurally intricate boronic esters. The reaction occurs

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

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

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• cyclization with participation of hydrazine and carbonyl functions leads to pyrazolylisoxazole D. Finally, condensation with second equivalent of hydrazine results in the target hydrazone 6. The synthetic utility of obtained 1,2,3-triazoles is demonstrated by its further derivatization. So, alkylation by MeI

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• by preventing overreduction [39]. While the metal-catalyst-free radical cyclization of alkene-tethered aryl halides has been well documented in the literature [40][41][42][43], the efficient intermolecular hydroarylation of alkenes still relies on the use of transition-metal catalysts, including Pd

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization. Keywords: atropisomer; Cope

• rearrangement; DFT calculations; diterpene; electrophilic cyclization; eunicellane; Introduction The eunicellane diterpenoids are a family of nearly 400 natural products that present a conserved 6/10-bicyclic hydrocarbon framework [1][2][3]. Mostly known from soft corals [2], but with a growing number of

• (1) [6]. In 1, the C2–C3 and C6–C7 alkenes are E-configured, with the latter alkene configuration being conserved in all known eunicellane cyclization mechanisms. The first trans-eunicellane synthase, AlbS from the biosynthesis of albireticulone in Streptomyces albireticuli [10], was also identified

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• second step of this reaction, regio- and stereochemically controlled intramolecular cyclization leads to the formation of versatile nitrogen-containing tricyclic systems. However, these useful organic transformations are usually carried out in highly toxic organic solvents such as benzene, toluene

• (Figure 3, path I) [132]. Similarly, Tomberg et al., note that in such reactions, amide is formed rapidly by opening the maleic anhydride ring first, followed by a slower cyclization [133]. On the other hand, according to the results of some DFT calculations, Naguib et al., state that [4 + 2

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• enabling the activation of small yet highly relevant organic substrates. For example, Huber and co-authors recently designed a Te-based catalyst in an indole Michael addition reaction [1][2][3][4][5]. Pale and Mamane utilized another Te-based catalyst in an electrophilic bromine-mediated cyclization

• reaction [6][7], and Gabbaï yet another in a different cyclization reaction [8][9], among other catalytic chalcogen bonding activation examples [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. In contrast, we have reported recently some redox-active Te-based catalysts

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• undergo cyclization reactions under mild conditions. In case of 1,3-diphenylacetone (4a) some activation of the methylene group is observed as well, because of benzylic stabilization. Dianions of 1,3-dicarbonyl compounds follow a different regioselectivity as compared to simple monoanions [6][7][8][9][10

• , we studied also cyclization reactions of chromones with heterocyclic enamines [30][31]. The present review aims to provide a personalized account of our work related to domino reactions of various types of chromones with carbonyl compounds, such as 3 and 4, and with 1,3-bis(silyloxy)-1,3-butadienes

• cyclization can be explained by the higher electrophilicity of the aldehyde as compared to the ketone. The yields were in general quite good (51–65%). Relatively low yields (51–52%) were obtained for chromones containing methyl substituents, presumably due to the lower electrophilicity of the chromone based

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines

• Stefan Jopp,
• Franziska Spruner von Mertz,
• Peter Ehlers,
• Alexander Villinger and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1246–1255, doi:10.3762/bjoc.20.107

• -bromoaniline (1a) and ethyl trifluoroacetoacetate (2), adapting a known procedure from Schlosser and Marull (Scheme 1) [17]. The cyclization of 1a with 2a chemoselectively afforded 8-bromo-2-trifluoromethyl-4-quinolone (3) rather than 8-bromo-4-trifluoromethyl-2-quinolone. Bromination of 3 with phosphoryl

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis

• Johannes Rocker,
• Till J. B. Zähringer,
• Matthias Schmitz,
• Till Opatz and
• Christoph Kerzig

Beilstein J. Org. Chem. 2024, 20, 1236–1245, doi:10.3762/bjoc.20.106

• with a quantum yield of 0.34. The pronounced triplet formation was exploited for the isomerization reaction of (E)-stilbene to the Z-isomer and the cyclization of cinnamyl chloride. Catalyst degradation mainly occurs through the long-lived Aza-H triplet (28 µs), but the photostability is greatly

• with its relatively high formation quantum yield and an energy of 2.32 eV can be used for isomerizing photoswitches like stilbene and for the cyclization of cinnamyl chloride. Our goal was not only to clarify the reaction pathway but also to provide a clear method for distinguishing between singlet and

• Information File 1). A remarkable turnover number of 4440 was achieved when 1 M stilbene was used (see Supporting Information File 1 for more information). Furthermore, the photocatalyst was utilized in a photosensitized cyclization reaction of cinnamyl chloride [84]. This photoreaction was originally

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• isoprenoid allylic carbocation has the capability to engage in standard carbocation reactions, including cyclization via intramolecular olefin attack at the positively charged center, Wagner–Meerwein rearrangements, and hydride or proton shifts. This sequence concludes either through deprotonation, resulting

• insecticidal activities [11], and are bio-fuel alternatives [12][13]. Sesquiterpene synthase can convert FPP to various terpenoids via different initial cyclization processes: 1,6-cyclization to yield the bisabolyl cation, 1,7-cyclization to form the cycloheptanyl cation, 1,10-cyclization lead to the

• germacradienyl cation, and 1,11-cyclization resulting in the humulyl cation [14][15]. Deprotonation of the intermediate germacradienyl cation yields germacrene A, a doorway towards the synthesis of many eudesmane and guaiane sesquiterpene hydrocarbons through its reprotonation-induced transannular reactions

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

• Manoel T. Rodrigues Jr.,
• Aline S. B. de Oliveira,
• Ralph C. Gomes,
• Amanda Soares Hirata,
• Lucas A. Zeoly,
• Hugo Santos,
• João Arantes,
• Catarina Sofia Mateus Reis-Silva,
• João Agostinho Machado-Neto,
• Leticia Veras Costa-Lotufo and
• Fernando Coelho

Beilstein J. Org. Chem. 2024, 20, 1167–1178, doi:10.3762/bjoc.20.99

• ][8][9][10][11][12]. The interest in the preparation of functionalized indanone derivatives has increased enormously, and many synthetic methods have been developed, including Friedel–Crafts cyclization reactions [13], cyclization of acetylenic derivatives [14], ring contractions and ring expansions

• [15], and the Nazarov reaction [16][17][18][19][20]. The Nazarov cyclization is one of the most versatile and simple methods for preparing indanones from aryl vinyl ketone derivatives [16][17][18][19][20]. The Nazarov reaction is classically formulated as a 4π conrotatory electrocyclization of a

• electrocyclization reaction could be mediated by weaker Lewis acids, and consequently a catalytic amount of them could be used. The first example of a catalytic version of the Nazarov cyclization was reported by Denmark and Jones [25][26][27][28][29][30][31]. They found that a substoichiometric amount of FeCl3 (40

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• compound E. Cyclization occurred via dehydrogenation and intramolecular aldol condensation and in the last step hydrogen transfer provided the desired cyclic product H (Scheme 35). In 2020, Maji and Adhikari reported a phosphine-free N,N-amine–manganese complex-catalyzed stereoselective intermolecular and

• control studies with Hg and TEMPO indicated that the reactions were homogeneous and did not proceed through a radical pathway. Synthesis of heterocycles via C–C and C–N bond formation In 2016, Beller and co-workers reported an intramolecular cyclization using 2-(2-aminophenyl)ethanol for the synthesis of