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

• . A comprehensive DFT investigation of reactant 6 was carried out to analyze the transition state of the IMDA reaction for a Br-substituted diene and its charge distribution (Figure 2). The diene has a notable positive charge (+0.318, +0.098, 6a), (+0.334, +0.082, 6h) and (+0.316, +0.074, 6r) whereas

• 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

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

• could be increased to a gram scale. Moreover, catalytic oxidation was also applied to prepare an electrophilic coupling partner. Gilmour and co-workers (2023) demonstrated the I(I)–I(III) catalytic cycle by using p-iodotoluene (cat 2) as the catalyst to activate 2-phenethyl-substituted 1,3-diene 148

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

• cycloaddition reactions with substituted furans as diene component to produce the corresponding epoxy-cycloaddition adducts. The authors developed an Ir/Sc tandem catalytic reaction to convert these adducts into polysubstituted 3-haloisoquinolines 99 in one pot. After obtaining isoquinoline compounds 99 with

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• not be proven. Overview of spectroscopic data of the newly synthesized compounds. The data given for the carbon analogues C-NBD1 (2-bromo-3-tosylbicyclo[2.2.1]hepta-2,5-diene) and C-NBD2 (N,N-diphenyl-4-(3-tosylbicyclo[2.2.1]hepta-2,5-dien-2-yl)aniline) were previously published [40]. Supporting

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

• 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

• 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

• involving the furan core in the cycloaddition, thus leading to the 2,3,3a,4,5,7a-hexahydro-1H-isoindole core 9. In the IMDA stage, the exocyclic diene system is involved (Scheme 5). The yields of the products listed below for the Ugi/Diels–Alder tandem reactions were 73% (9a) and 70% (9b). The structures of

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

• acetylacetone from the inner vial into the outer vessel containing formaldehyde, which affected the yield of all [4 + 2]-cycloaddition adducts involving this CH acid, regardless of the choice of diene. For acetoacetic ester and 1,3-diphenylpropane-1,3-dione, it was found that in addition to the main products 5

• due to the addition of another equivalent of active methylene compound were also observed. Among the reactions studied, the diffusion mixing method gave the highest yield when using Meldrum’s acid as CH acid and in reactions with cyclopentadiene as diene. Experimental Materials and methods All

• (1 equiv), 0.05 mmol ʟ-proline and 2.0–5.0 mmol diene (2–5 equiv) in 3–5 mL acetonitrile was placed into a 15 mL vial (diameter 1.3 cm). This vial was then placed into a closed 50 mL vial (diameter 2.8 cm) containing 3–5 mL of formalin, and the reaction mixture was stirred at room temperature for 2

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

• orientation between the electron-rich nitrogen of the diene and the electron-poor carbon of the alkyne. A different one-pot procedure affording tetrahydropyridines was developed employing two molecules of aromatic aldehydes, ethyl acetoacetate and two molecules of aniline. The copper triflate catalyst acts in

Synthesis, structure and π-expansion of tris(4,5-dehydro-2,3:6,7-dibenzotropone)

• Yongming Xiong,
• Xue Lin Ma,
• Shilong Su and
• Qian Miao

Beilstein J. Org. Chem. 2025, 21, 1–7, doi:10.3762/bjoc.21.1

• synthesized according to the procedures detailed in Supporting Information File 1. In this reaction, the first step of diazo–thioketone coupling occurred at 50 °C in THF, and the second step of desulfurization with triisopropyl phosphite occurred in refluxed toluene, giving diene 10 in a yield of 47%. The

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

• construction of carbon–carbon bonds [5][6][7][8][9][10]. The hetero-Diels–Alder reaction is therefore an attractive strategy for the synthesis of heterocyclic compounds. It involves the reaction of dienes or dienophiles which possess a heteroatom in their structure. In this reaction, the HOMO of the diene and

• 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

• nitrogen atom which is prone to interacting with hydrogen-bond donors or Brønsted acids decreasing the LUMO energy of the diene. This review article aims to give an overview of the non-covalent organocatalyzed cyclization reactions involving α,β-unsaturated imines. Although most of the cyclization

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

• hetero-Diels–Alder reaction of Danishefsky's diene 6 with p-nitrobenzaldehyde (7, Figure 2). The reaction can provide three products depending on the reaction conditions; either a Mukaiyama aldol (8) or products of Diels–Alder cycloaddition (9 and 10). Out of the three screened catalysts, only calix[4

• orientation of p-nitrophenyl units, due to the shielding of the bound aldehyde substrate from the incoming diene. The catalytic inactivity of 5 demonstrated the requirement of macrocyclic character for the potential catalysts. Later in 2009, the same group reported an organocatalyzed diastereoselective aldol

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

• -peroxyamides 148 with TBHP and formamide derivatives 147 by difunctionalization of 1,3-diene, 1,3-enynes as well as styrenes 146 (Scheme 46) [110]. The iron catalyst is believed to mediate the formation of tert-butoxy and tert-butylperoxy radicals. The former abstracts the hydrogen atom from the formyl C–H

• reaction of iodine and TBHP forms tert-butoxy radical and tert-butylperoxy radical A. Addition of tert-butylperoxy radical A to diene 220 results in the stable allyl radical B, which reacts with iodine radical to form iodoperoxide C. Elimination

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

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

• ) (Scheme 18). 17-Spiro-1,3-oxazoline steroids Jin et al. [37] described a series of spiro-1,3-oxazolines synthesized from the commercially available estrane derivative ethylene deltenone 24. This conjugated diene was regioselectively epoxidized at the 5(10) double bond to furnish compound 58

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

• prenyltransferase (PT) domain located at the C-terminus of BscA (Scheme 2A). Subsequently, the terpene cyclase (TC) domain at the N-terminal of BscA generates fusicocca-2,10(14)-diene (6), which bears the common 5/8/5 fused tricyclic scaffold common to this natural products family. Sequential oxidative conversions

• tolerance through enzyme mutagenesis should allow more precise control over scaffold-constructing reactions. As with the related natural products, hybrid sorbicillinoids were also known to be biosynthesized through Diels–Alder reactions between diene 34 and non-sorbicillinoid-derived dienophiles [29

• 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

• reaction with 5,6-unsubstituted 1,4-dihydropyridine. Keywords: [3 + 2] cycloaddition; cyclopenta-1,3-diene; cyclopenta[4,5]pyrrolo[2,3-b]pyridine; 1,4-dihydropyridine; electron-deficient alkyne; isocyanide; Introduction Isocyanide is a unique and attractive functional group in organic chemistry. The

• intermediate B. Thirdly, the intramolecular coupling of the positive charge and the negative charge in intermediate B resulted in the formation of polysubstituted 5-(alkylimino)cyclopenta-1,3-diene intermediate C, which has been described in several papers about the reaction of alkyl isocyanides and electron

• -deficient alkynes [59][60][61][62][63]. The in situ generated cyclic intermediate C has a resonance hybrid C’. Then, the further nucleophilic addition of the electron-rich enamino unit to 5-(alkylimino)cyclopenta-1,3-diene intermediate C gave intermediate D. At last, the coupling of the iminium cation with

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

• of diversity-oriented synthesis of N-heterocycles via sequential multicomponent approaches, we envisioned that α-aminoacetals could act as bifunctional building blocks along with 1,2-diaza-1,3-diene (DD) coupling partners [22][23], in obtaining functionalized N-aminohydrazones as key intermediates

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

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• (silyloxy)-1,3-butadienes are highly moisture sensitive compounds which can be prepared from the corresponding 1,3-dicarbonyl dianions in two steps. For example, diene 6a is available by silylation of 2 to give silyl enol ether 5 which is subsequently deprotonated by LDA and treated with

• the chromone and at carbon C-4 of the diene. However, in case of a benzyl and a benzyloxy group located at carbon C-4 of the diene, the overall yields were rather low (20%). This might be explained by steric effects. One of the best yields was obtained for the reaction of diene 6a with unsubstituted

• chromone 9a and for the diene containing a methoxy group (R4 = OMe). The products proved to be interesting, due to their blue fluorescence. 3-Formylchromones Dimethyl acetone-1,3-dicarboxylate The reaction of 3 with 3-formylchromones 10a–d afforded benzophenones 19a–d in moderate to good yields (Scheme 5

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

• 9 and the quinone derivative 2,5-bis((2-methoxyphenyl)amino)cyclohexa-2,5-diene-1,4-dione (10) were isolated from the mixture. The spectroscopic data were consistent with earlier reports on the direct synthesis of 9 [50][51] and 10 [52]. The mass spectrum of oxamide 9 showed peaks corresponding to

• similar mechanism may be assumed for the formation of the other oxamides 9 and 13. Mechanism for the formation of 2,5-bis((2-methoxyphenyl)amino)cyclohexa-2,5-diene-1,4-dione (10) Generally, formation of polyaniline occurs through a radical mechanism. Such a radical mechanism is relevant for the formation

• radical resulting from reaction of o-anisidine with SeO2 is stabilized by resonance (Scheme 7). It combines with the hydroxyl radical and undergoes subsequent oxidation to give 2-methoxycyclohexa-2,5-diene-1,4-dione. This iminoquinone upon hydrolysis gives 2-methoxycyclohexa-2,5-diene-1,4-dione, and the

Novel route to enhance the thermo-optical performance of bicyclic diene photoswitches for solar thermal batteries

• Akanksha Ashok Sangolkar,
• Rama Krishna Kadiyam and
• Ravinder Pawar

Beilstein J. Org. Chem. 2024, 20, 1053–1068, doi:10.3762/bjoc.20.93

• we report our attempt to enhance both the thermochemical and photophysical properties in a single-bridged bicyclic diene (BBD)-based photoswitch by elongating the unsaturated bridge with different heteroatomic units. To elucidate the best elongation unit, the energy storage capacity and the TBR

• /kg), and TBR barrier (121.76 kJ/mol) of prototype NBD/QC in the gas phase. The outcomes render useful insights into the stability and properties of bicyclic diene-based photoswitches having elongated unsaturated bridges and indeed paves the way for the rational design of practical MOST systems

• . Keywords: bridged bicyclic diene (BBD); molecular solar thermal (MOST) energy storage; reversible photoswitches; unsaturated bridge elongation; Introduction Energy is an inevitable necessity of society and its rate of consumption is continuously increasing across the world due to increasing population and

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

• strategy has been previously used in probe development [9][16][17], no one has reported it previously with furans. This is likely because utilizing a furan ring as the diene source can be quite challenging. Furans are aromatic molecules, resulting in these five-membered ring systems being relatively

• 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

• oxygen atom in the ring destabilizing the diene HOMO. Thus, when it comes to substituents on a furan ring, it is better to place electron-withdrawing groups in the three and/or five positions of the furan to aid in the natural flow of the electrons [19]. Due to this reactivity, we expected that a Diels

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• starting from nitro compounds with one or two double bonds in the suitable position. The process has been generalized using nitro compounds substituted on the aromatic ring with electron-donating and electron-withdrawing groups. Also the synthesis of 4,4′-diaza-3,3′-bi-1H-indole from 2,2'-(buta-1,3-diene

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• synthesis of various polysubstituted BCHs, including 1,3-BCHs 96a and 96b via an intramolecular [2 + 2] cycloaddition from the corresponding diene 97 (Scheme 10) [34]. No comparative physicochemical or biological data was collected. 1,4-Disubstituted bicyclo[2.1.1]hexanes 1,4-Disubsituted bicyclo[2.1.1

• planarity. Brown and co-workers prepared the [2]-ladderanes via a multistep sequence from diene 147 including an intramolecular [2 + 2] cycloaddition (to (±)-148) and a Wolff rearrangement (to (±)-150) (Scheme 16A) [63]. This approach yielded predominantly the endo diastereomer of trans-[2]-ladderanes 150

• -workers, and was accessed over 8 steps from diene 161 (Scheme 17A) [51]. Diels–Alder reaction of diene 161 and di-tert-butyl azodicarboxylate (160) followed by palladium-assisted elimination of acetic acid gave diene 162. A sequence of 4π-electrocyclisation and electrophilic transcarbamation (to 163

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε

• -substituted dienes 2b and 2c were suitable for this MCR, affording the 1,4-addition products 4l and 4m albeit with moderate regioselectivity (1,4-/1,2-addition = 2:1). To our delight, the reactions with 2,3-disubstituted diene 2d and 1,4-disubstituted diene 2e also readily provided products 4n and 4o. In the

• , the corresponding 1,2-addition products 4p–t were formed with high selectivity (E/Z > 20:1, 1,2-/1,4-addition >20:1), presumably due to steric hindrance by the phenyl group. Furthermore, the 1,3-diene bearing a 1-furan group with smaller steric hindrance afforded product 4u with moderate

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• -1,1,1,4,4,4-hexafluorobut-2-enes have been investigated. A simple, one-pot procedure for the preparation of a new allene (1,1,4,4,4-pentafluorobuta-1,2-diene) and some of its transformations is presented. Keywords: allenes; dehydrohalogenation; halogenation; 1,1,1,4,4,4-hexafluorobut-2-enes; isomerization

• compound, but led to the elimination of two fluorine atoms with the formation of 1,1,4,4-tetrafluorobuta-1,3-diene [9]. It was also shown that the reactions of the boron reagent (CAACMe)BH2Li(thf)3 with hydrofluoroolefins, including (Z)-1,1,1,4,4,4-hexafluorobut-2-ene, results in defluoroborylation to form

• agreement with the published data [23]. The most interesting outcome from our point of view was the formation of 1,1,4,4,4-pentafluorobuta-1,2-diene (11). 1,1-Difluoroallenes are building blocks for a great number of valuable transformations [28]. Therefore, the synthesis of new fluorinated allenes