A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• the dienophile presents a negative charge (−0.280 to −0.325, 6a), (−0.280 to −0.327, 6h) and (−0.280 to −0.327, 6r), respectively. This structure induces electrostatic repulsion instead of the requisite attraction for a successful interaction between the electron-rich diene and the electron-deficient

• dienophile, characteristic of Diels–Alder processes. The incorporation of a bromine atom at the 5-position of the diene (+0.306, −0.041, 6j) complicates the situation. As an electronegative element, Br exerts an inductive electron-withdrawing influence to enhance the electron shortage of the diene. This

• electronic imbalance reduces the diene's nucleophilicity, rendering it less reactive to the dienophile. The unfeasibility of the IMDA reaction in this system arises from inadequate interatomic distances, electrostatic repulsion from incompatible associated dienophile was conducted [19][20]. Firstly, the

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• under the Ugi reaction conditions (Scheme 1). A furan double bond and an exocyclic double bond, forming the diene, enter the intramolecular cyclization, and a residue formed by the monoanilide of maleic acid acts as a dienophile. Notably, non-cyclized Ugi adducts A1 were not found in the products. The

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• formaldehyde (generated from paraformaldehyde upon heating), an adduct of a methylidene derivative of a CH acid dienophile was detected in some cases only in reference [15] (when carrying out the reaction in a sealed tube in the presence of copper(II) acetate). However, in most reactions only the hetero-Diels

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

• the LUMO of the dienophile interact to construct the six-membered heterocyclic derivative and the reaction requires electron-rich dienes and electron-poor dienophiles (Figure 2a). In the inverse electron demand hetero-Diels–Alder reaction (IEDHDA), the LUMO of the diene interacts with the HOMO of the

• dienophile, and therefore it proceeds through the reaction of electron-poor dienes and electron-rich dienophiles (Figure 2b). α,β-Unsaturated imines can undergo inverse electron demand aza-Diels–Alder reactions (IEDADA) to produce N-heterocyclic compounds. The search for an enantioselective pathway to carry

• the squaramide moiety and a nucleophile through deprotonation as Brønsted base. On the other hand, a chiral phosphoric acid provides a confined chiral environment where the reactants are approached, activating both the azadiene by interaction with the acidic hydrogen and a dienophile bearing a

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

• ether 39, a ring-closing enyne metathesis (RCEYM) was initiated using the Grubbs second-generation catalyst (G-II) and high temperature to obtain the spiro 2,5-dihydrofuran derivative 40 in 76% yield. Additionally, when a dienophile such as N-phenylmaleimide was directly added to the same pot and

• derivatives, affording products in yields ranging from 10% to 91%, depending on the structure of the dienophile. Spiropyrrolidine steroids Numerous dispiropyrrolidine derivatives have been reported on various steroidal nuclei, particularly at C-16. Raghunathan and Babu were the first to describe the synthesis

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

• ]. Gulder and co-workers achieved the total synthesis of hybrid sorbicillinoids using the established chemo-enzymatic synthetic process, in addition to the synthesis of homodimers (Scheme 4B). Upon treatment of the extract of the enzymatic reaction mixture containing (S)-34 with dienophile 39, sorbicatechol

• (40) was obtained in 30% yield from 33. The use of dienophile 41 instead of 39 led to the concise total synthesis of rezishanone B (42) in 32% yield. The same research group has also facilitated rapid access to bisorbicillinoid analogs, by using either various dienophiles or non-natural type

• phenol 46 yields moracin C (47). As the final steps in the biosynthesis of 3, oxidation of the prenyl group of 47 to diene 48 and the subsequent DA reaction with dienophile 44 should theoretically be catalyzed by oxidase and Diels–Alderase, respectively. However, despite effort over several decades

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• can act as an activated enamino unit and electron-rich dienophile to take part in some synthetic reactions [36][37][38][39]. In recent years, 5,6-unsubstituted 1,4-dihydropyridines have been recognized as the reactive electron-rich dienophiles, which proceeded several Povarov reactions with various 1

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

• conditions [113]. Both diene and dienophile systems are readily soluble in the reaction medium of interest under the conditions studied, in contrast to aqueous media. The non-polar aprotic nature of vegetable oils and wax esters makes them inert to many reagents, as in this study. The reaction was completed

Kinetically stabilized 1,3-diarylisobenzofurans and the possibility of preparing large, persistent isoacenofurans with unusually small HOMO–LUMO gaps

• Qian Liu and
• Glen P. Miller

Beilstein J. Org. Chem. 2024, 20, 1099–1110, doi:10.3762/bjoc.20.97

• persistence associated with isoacenofurans is of great concern if these molecules are to be utilized as organic semiconductors. Likewise, Hamura and co-workers’ 1,3-diphenethynylisobenzofurans were fleeting intermediates that could not be isolated, but were instead trapped in situ by a suitable dienophile [4

• switching the dienophile from DMAD to acrylonitrile. Once again, compounds 3 and 23 were unreactive, even after 184 hours of reaction time with a 13,500-fold excess of acrylonitrile. The reaction between 3 and a large excess of DMAD (116 equivalents) in boiling toluene (111 °C) was also studied by 1H NMR

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• furans. While the frontier molecular orbital theory can be applied to this cycloaddition reaction, the thermodynamics must also be taken into consideration. Most Diels–Alder reactions with furans as the diene follow normal-electron-demand with the diene HOMO reacting with the dienophile LUMO due to the

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• pristine acene with a dienophile to transiently form a cycloadduct with increased solubility for processing purposes, and unmasking it afterwards via a retro-Diels–Alder reaction [16][17][18][19]. In parallel to retro-Diels–Alder reactions, another efficient strategy for the in situ aromatization of target

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• ) [119]. The quantitative CDA reaction progression was attributed to be due to the presence of multiple cyano groups on the skeleton, which increased the dienophile character of the cyano groups and stabilized the structure of the product. The thermal conversion of 40 to 41 was also accelerated by the

Biphenylene-containing polycyclic conjugated compounds

• Cagatay Dengiz

Beilstein J. Org. Chem. 2023, 19, 1895–1911, doi:10.3762/bjoc.19.141

• naphthazarin and triptycene units (Scheme 14) [48]. Naphthazarin derivatives are known to complex with boron moieties and metals to form electron-poor acene units. Through the Diels–Alder reaction involving dienophile 66, which was formed via the tautomerization of compound 65, and diene 67, compound 68 was

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• preferred to maximize orbital overlap (Figure 4) [63]. For π-acidic surfaces, the exo transition state VII is more completely accessible (Figure 4). The 3-hydroxy-2-pyrone (24) was selected as representative diene for the anionic [4 + 2] cycloaddition with maleimide 25 as standard dienophile to afford endo

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

• Xiu-Yu Chen,
• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• behaved as an activated electron-rich dienophile. Inspired by these elegant synthetic methodologies and in continuation of our aim to develop well-known Huisgen 1,4-dipoles for the construction of diverse nitrogen-containing heterocyclic compounds [45][46][47][48][49][50][51][52][53][54][55][56][57][58

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• acetylenes in Diels–Alder reactions [49], since desulfonylation of the cyclohexene-disulfones with sodium amalgam or samarium(II) iodide affords 1,4-cyclohexadienes (Scheme 8). In a comparative study by Nakayama [50], the dithiin-type cyclic disulfone 7 emerged as a much stronger dienophile than any other

• analog 26 should also be a reactive dienophile [51], but is a less useful building block, as it reacts twice and the adducts will not be as easily desulfonylated. The dienophile 7 reacts with a wide range of dienes at room temperature, without the need for a Lewis acid catalyst. This is particularly

• -derived dienophile 27 can be used as a ‘linchpin’ reagent (Scheme 8c), as a first Diels–Alder reaction can be followed by a straightforward base-promoted β-elimination of the chloride, releasing another reactive dienophile. This way, highly congested ring systems can be built up around the dithiin ring

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• . Mechanochemical palladium-catalyzed borylation protocol of aryl halides. 1,2-Debromination of polycyclic imides, followed by in situ trapping of the dienophile by several dienes. Synthesis of g-h-PCN from sodium phosphide and trichloroheptazine mediated by mechanochemistry. Mechanochemical intra- and

Dienophilic reactivity of 2-phosphaindolizines: a conceptual DFT investigation

• Nosheen Beig,
• Aarti Peswani and
• Raj Kumar Bansal

Beilstein J. Org. Chem. 2022, 18, 1217–1224, doi:10.3762/bjoc.18.127

• >Y=P– functionality of 2-phosphaindolizines (dienophile). Supporting Information Supporting Information File 260: Cartesian coordinates of the geometries optimized (Table S1) at the B3LYP/6-31+G (d) level of theory. Acknowledgements The computational facilities provided by the IIS (deemed to be

Radical cation Diels–Alder reactions of arylidene cycloalkanes

• Kaii Nakayama,
• Hidehiro Kamiya and
• Yohei Okada

Beilstein J. Org. Chem. 2022, 18, 1100–1106, doi:10.3762/bjoc.18.112

• reaction is a typical example of this activation mode since both the original diene and dienophile are electron-rich and thus not an effective combination of reactants [1][2][3][4][5][6][7][8][9][10][11]. Single-electron transfer makes the construction of six-membered ring systems possible. In general

• , single-electron oxidation of an electron-rich dienophile generates its radical cation which is then trapped by the diene (Figure 1). Since the forming cyclohexene remains in the radical cation state as well, one electron reduction is required to complete the net redox neutral transformation. Therefore, a

• chain pathway can be involved, where an electron acts as a catalyst rather than a reagent [12][13][14][15][16][17][18]. In this reaction format, trans-anethole is an electron-rich dienophile and has widely been studied as a benchmark for single-electron transfer using photochemical and electrochemical

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• . On the other hand, the tetrahydrospiro[carbazole-3,5'-pyrimidine] 4 can be converted to aromatized spiro[carbazole-3,5'-pyrimidine] 3 through the oxidation of DDQ. In the absence of the effective dienophile, the normal Friedel–Crafts alkylation of 2-methylindole with aromatic aldehyde gives the well

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• 2002, an interesting methodology for menadione synthesis was reported by Kacan and Karabulut (Scheme 5). The authors studied a Diels–Alder reaction, using LiClO4-diethyl ether (LPDE) as a catalyst, 1-ketoxy-1,3-butadiene 28 as a diene and 2-methyl-1,4-benzoquinone (29) as dienophile. By this method

• -benzoquinones and p-hydroquinones or the synthesis of menadione (10). The furan derivative 34 was used as a diene and 2-iodophenyltrifluoromethanesulfonate (35) as a dienophile, in the presence of n-butyllithium, forming 10 in 55% yield (Scheme 8) [92]. In the same year, Gogin and and co-workers developed a

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• the sterically less demanding N-propylphthalimide was used, only the 9,10-adduct was formed, which indicated that the steric bulkiness of the N-substituent in the dienophile also affected the 1,4-site-selectivity. It is very intriguing that when a different kind of square-pyramidal bowl host B was

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• % (R)-CPA 2, the benzyl-substituted 3-alkenylindole 81 (dienophile) was subjected to a Povarov cycloaddition with the commonly used imine 80, giving the 2,3,4-tetrahydroquinoline as a single diastereomer in high yield and enantioselectivity and finely tolerating the high steric requirements necessary

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

• Ren-Jie Fang,
• Chen Yan,
• Jing Sun,
• Ying Han and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159

• 3-(indol-3-yl)-1,3-diphenylpropan-1-one gave the expected indole-substituted chalcone A, which comprises the desired 3-vinylindole scaffold as the reactive diene. In the meantime, the carbonyl group of the chalcone is protonated to give the activated dienophile in the presence of p-toluenesulfonic

• acid. Secondly, the Diels–Alder reaction of indole-chalcone A with the dienophile results in the tetrahydrocarbazole B having an exocyclic C=C bond. Thirdly, a new tetrahydrocarbazole intermediate C is formed by a 1,3-H shifting process. The resulting tetrahydrocarbazole intermediate (C) might be a