Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• into the pentacyclic diene intermediate 93 via a two-step sequence. Subsequent [4 + 2] cycloaddition of 93 with singlet oxygen yielded an unstable endoperoxide adduct 94, which rearranged to diketone 95. A five-step sequence, featuring an intramolecular aldol reaction to assemble the pentacyclic core

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• is as follows: Starting from the chiral compound (S)-carvone, four simple transformations yield the enone intermediate 11. This intermediate undergoes an intermolecular [4 + 2] cycloaddition with diene 12, generating two sets of regioselective products in an approximate ratio of 1:1. The product with

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• aldehyde 53 [39] (Scheme 10). The key steps in this synthesis are based on an asymmetric rhodium-catalyzed [4 + 2] cycloaddition reaction [40], followed by a unique benzilic acid-type rearrangement under very mild conditions [41]. A step-by-step mechanism for the benzilic acid-type rearrangement of

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• 56a (Scheme 9) – formed via [4 + 2] cycloaddition of singlet oxygen with the southern furan moiety in gracilisoid F (54) and gracilisoid H (56), respectively – served as branching points in the downstream divergent synthesis. Kornblum–DeLaMare-type rearrangement of 54a and 56a assembled gracilisoids B

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• Griesbeck reported the tetraphenylporphin-photosensitized oxygenations of furan and derivatives in non-polar aprotic solvents, yielding the corresponding monomeric unsaturated secondary ozonides through a (4 + 2) cycloaddition of singlet oxygen onto the diene linkage of the furan ring. The attack of a

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• transformation involving acyl-group migration, [4 + 2] cycloaddition and aromatic Pummerer-type reaction, provided chiral spiro compound 59 with the 6/6/5/5/6/6 scaffold, and this intermediate was further elaborated to 60 in six additional steps. Lipases from Pseudomonas genus Pseudomonas is a genus of Gram

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• the FeIII species. An alternative mechanism involving a concerted [4 + 2] cycloaddition between the aza-butadiene moiety in II and the alkene, leading to intermediate IV, cannot be ruled out. Conclusion In summary, we have successfully developed a highly efficient method for the oxidative C–C bond

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

• scaled up to a gram scale operation. Similarly, Liu and co-workers (2020) reported a Ag2O-catalyzed ring-opening of cylopropenone 309 with oximes to give the corresponding series of novel 1,3-oxazinones 330–332 in good yields. The reaction involves a [4 + 2] cycloaddition (334) of the fragmented

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

• reaction and Diels–Alder [4 + 2] cycloaddition based on vinylfuran and 1,3-butadienylfuran derivatives was designed and studied. It was found that in the case of 3-(furan-2-yl)acrylaldehyde, a one-pot Ugi reaction and intramolecular Diels–Alder vinylarene (IMDAV) reaction leads to the formation of the

• present work, the new tandem sequence involving an Ugi reaction and Diels–Alder [4 + 2] cycloaddition based on vinylfuran, 1,3-butadienylfuran derivatives was designed and studied. Results and Discussion To carry out an intramolecular Diels–Alder reaction, we tested (E)-3-(furan-2-yl)acrylaldehyde (1a) in

• the Ugi reaction with a maleic acid to form adducts containing both, diene and dienophilic fragments. It was found that aldehyde 1a reacted with amines 2, isonitriles 3, and maleic acid monoanilide (4a) to form an adduct that spontaneously underwent a [4 + 2] cycloaddition giving furoisoindoles 5a–h

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

• main reaction products. Keywords: aldol condensation; [4 + 2]-cycloaddition; diffusion mixing; formaldehyde; Knoevenagel condensation; three-component reactions; Introduction Formaldehyde is a reactive electrophilic reagent widely used as a C1 building block in multicomponent reactions [1][2][3]. Its

• various CH acid derivatives and conjugated dienes (cyclopentadiene, 1,3-cyclohexadiene, 2,3-dimethylbutadiene and isoprene), leading to [4 + 2]-cycloaddition adducts (Scheme 1). It should be noted that in previous works describing three-component reactions of carbonyl compounds, conjugated dienes and

• –Alder products were isolated from the reaction mixtures. In the present study, we carried out similar three-component reactions under significantly milder conditions (room temperature), and the main or only [4 + 2]-cycloaddition products in most cases were carbocyclic ones. Results and Discussion

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

• axially chiral pyrroles and indoles 44 are obtained (Scheme 14). Zhu and co-workers developed a method for the atroposelective formation of arenes 48 by an NHC-catalyzed formal (4 + 2) cycloaddition [34]. The triazolium pre-catalyst (R,S)-C11 was the most efficient in providing a range of biaryls in high

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

• methodologies of 1-azadienes involve a formal [4 + 2] cycloaddition (IEDADA reaction) to construct six-membered nitrogen-containing molecules, α,β-unsaturated imines can also behave as C4 synthons involved in (4 + 1) and (4 + 3) cycloadditions or they act as C2 synthons undergoing (2 + 3) cycloadditions for

• ) and good to excellent enantioselectivities (60–97% ee) when using organocatalyst III. Later, in 2018, Zhou and co-workers developed a bifunctional squaramide-catalyzed enantioselective formal [4 + 2] cycloaddition of benzofuran-derived azadienes 11 with malononitrile (12) [26]. This work provides an

• diastereomers 40 with moderate yields (34–61%) and moderate enantioselectivities (55–66% ee). In this case, the addition of tetramethylguanidine (TMG) was necessary to promote the cyclization. This work is one of the first reports in which an enantioselective [4 + 2] cycloaddition of 1-azadienes was performed

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

• , Tomilov et al. described the formation of tetrahydropyridazine 3,4,5,6-tetracarboxylic esters in 42% yield upon the decomposition in chloroform at 60 °C of methyl diazoacetate in the presence of pyridine and catalyzed by rhodium(II) acetate (Scheme 1b) [24][25]. More recently, an unusual [4 + 2

• ]-cycloaddition reaction between electron-poor 1,2-diaza-1,3-dienes and electron-poor alkenes in refluxing acetonitrile was reported leading to various substituted tetrahydropyridazines in 17–78% yields (Scheme 1c) [26][27]. Nevertheless, these methods are neither relevant for the synthesis of 1 nor appropriate

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

• a [4 + 2] cycloaddition process [45]. Very recently, we also found that base-promoted [4 + 2] cycloaddition of salicyl N-tosylimines and 5,6-unsubstituted 1,4-dihydropyridines resulted in novel tetrahydrochromeno[3,2-b]pyridine derivatives in satisfactory yields [46]. Inspired by these efficient

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

• (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

• ] cycloaddition between maleic anhydride and secondary amine occurs first, followed by the corresponding amidation (Figure 3, path II) [110]. Although IMDAF reactions involving furan systems bearing amide functionality are generally reversible [134], the formation of the addition products in high yields in this

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

• , respectively. In addition to the substrates that did undergo the Diels–Alder [4 + 2] cycloaddition, some substrates were unable to react with our chemical probe. For example, 18 did covalently attach to the probe, but there is no 18 leftover to quantify the amount of conversion. Additionally, the mass spectrum

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

• , subsequent RE affords 7. Conversely, if the formal [4 + 2] cycloaddition occurs along the course elucidated in path B, the generation of 8 is expected. Similarly, when the formal [4 + 2] cycloaddition follows the course depicted in path C, the generation of 9 is envisaged. Among these compounds, 10 features

• + 2] cycloaddition reaction with the anthracene moiety, yielding the DA cycloadduct 17. To achieve the conversion of the alkyne moiety of 16 into TCBD, the addition of five equivalents of TCNE to 16 or one equivalent of TCNE to 17 is required. This results in the formation of TCBD compound 18 bearing

• agent for TCNE. Anthracene-based ynamide 16 offers two potential reactive sites for TCNE, one residing at the anthracene moiety and other at the alkyne moiety, as shown in Scheme 9 [71]. As exemplified by Trolez et al., the introduction of one equivalent of TCNE to 16 at room temperature initiates a [4

Biphenylene-containing polycyclic conjugated compounds

• Cagatay Dengiz

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

• reaction, followed by a Au(I)-catalyzed [4 + 2] cycloaddition reaction to afford the target substrate 96 and its regioisomer 95 in a 2:1 ratio (Scheme 20). POA 87 was obtained on Au(111) at 610 K after Ullmann-type coupling and aromatic dehydrogenation of compound 96. Apart from these studies, the

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

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• are available [2][3], only a couple of cycloaddition reactions has been reported [4]. For example, [3 + 2] dipolar cycloadditions to form saturated difluoroisoxazolidines [5][6] and difluoropyrrolidines [7] and [4 + 2] cycloaddition reactions with gem-difluoro-1,3-dienes [8]. The overall landscape of

Construction of hexabenzocoronene-based chiral nanographenes

• Ranran Li,
• Di Wang,
• Shengtao Li and
• Peng An

Beilstein J. Org. Chem. 2023, 19, 736–751, doi:10.3762/bjoc.19.54

• Sonogashira cross-coupling reaction of phenylacetylene 50 and 1,4-dibromotetrafluorobenzene. The resulting bis[aryl(ethynyl)]tetrafluorobenzene 59 was able to undergo a 2-fold [4 + 2] cycloaddition reaction with cyclopentadienone 2, affording polyaromatic 60 in a 70% yield. The final step was the Scholl

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

• single-cis conformation. Ando and co-workers prepared the symmetrical 1,4-dithiane 41 (Scheme 9a) [55], and amply illustrated the concept by reacting it in a [4 + 2] cycloaddition with a highly reactive diazo dienophile (Cookson’s reagent or 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD)) to afford the bis

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• recently, the same group developed an efficient Rh(III)-catalyzed C–H cross-coupling of enaminones with diazodicarbonyls for the divergent construction of isocoumarins and naphthalenes [27]. Moreover, Loh et al. disclosed a Rh-catalyzed formal [4 + 2] cycloaddition of enaminones with diazocarbonyls [28

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• investigated for FPDs: the [4 + 2] cycloaddition with alkenes resulting in pyran-annulated products [27][28][29][30][31][32][33][34] and the [3 + 2] cycloaddition with nitrones resulting in isoxazole-annulated products [35][36][37] (Scheme 2). However, formal [4 + 1] cycloaddition reactions for FPDs remain to

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• reactions that were first known from synthetic chemistry, e.g., pericyclases can promote pericyclic reactions such as [4 + 2]-cycloaddition, also known as Diels–Alder reaction [3]. In fact, most named reactions in organic chemistry originally discovered by synthetic chemists have an analogy in nature