Knoevenagel condensation of 4,5- and 1,8-diazafluorenes

• Darya S. Cheshkina,
• Christina S. Becker,
• Alina A. Sonina and
• Maxim S. Kazantsev

Beilstein J. Org. Chem. 2026, 22, 803–812, doi:10.3762/bjoc.22.62

• malononitrile or acetonitrile derivatives [14][19][20]. However, the use of diazafluorenes as the methylene component in condensation reactions remains underexplored. These reactions can be carried out under basic [13][21], acidic [3][5] or Lewis acid catalysis [15][22], but the corresponding literature

Symmetrical D–π–A–π–D indanone dyes: a new design for nonlinear optics and cyanide detection

• Ergin Keleş,
• Alberto Barsella,
• Nurgül Seferoğlu,
• Zeynel Seferoğlu and
• Burcu Aydıner

Beilstein J. Org. Chem. 2026, 22, 131–142, doi:10.3762/bjoc.22.6

• important parameter for compounds used in electro-optic (EO) application, were determined by thermogravimetric analysis (TGA). Results and Discussion Syntheses In the first step, 2-(1,3-dihydro-2H-inden-2-ylidene)malononitrile (1) was synthesized by indan-2-one and malononitrile in DCM with ammonium acetate

• /acetic acid buffers with a good yield (84%). Target compounds were synthesized by a coupling reaction between 2-(1,3-dihydro-2H-inden-2-ylidene)malononitrile (1) and appropriate alkylaminobenzaldehyde derivatives in acetic anhydride. Compounds were obtained with low to good yields (25–75%, conventional

Highly electrophilic, gem- and spiro-activated trichloromethylnitrocyclopropanes: synthesis and structure

• Ilia A. Pilipenko,
• Mikhail V. Grigoriev,
• Olga Yu. Ozerova,
• Igor A. Litvinov,
• Darya V. Spiridonova,
• Aleksander V. Vasilyev and
• Sergey V. Makarenko

Beilstein J. Org. Chem. 2026, 22, 123–130, doi:10.3762/bjoc.22.5

• trichloromethylnitrocyclopropanes based on the well-known 1-bromo-1-nitro-3,3,3-trichloropropene (1). Results and Discussion It turned out that the synthesis of the target trichloromethylnitrocyclopropane 2 based on the reaction of 1-bromo-1-nitro-3,3,3-trichloropropene (1) with malononitrile under conditions similar to those

• summary, we proposed a diastereoselective method for the synthesis of vicinal trichloromethylnitrocyclopropanes by forming a cyclopropane ring from a trichloromethylnitroethene substrate and an active methylene component. Variation of the methylene component structure – linear (malononitrile, methyl

• -fused trichloromethylnitrocyclopropane 6. Synthesis of spiro-fused trichloromethylnitrocyclopropanes 7–9. i: 1.5 AcOK, MeOH, rt, 3 h. Main NOE correlations in 9a, 9b. Proposed mechanism of the formation of trichloromethylnitrocyclopropanes. Reaction of compound 1 with malononitrile leading to

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• malononitrile to form benzylidenemalononitrile (BMN). In a typical primary amine-catalyzed Knoevenagel condensation, the amine would undergo imine condensation with benzaldehyde. The imine would then deprotonate malononitrile, and the resulting carbanion would react with the imine, releasing the final product

• and the amine catalyst (Scheme 1A) [47][48]. However, there is another possible mechanism where malononitrile is deprotonated by the amine catalyst. Here, the resulting carbanion would attack benzaldehyde to form 2-(hydroxy(phenyl)methyl)malononitrile (HPMM) as an intermediate that then loses a water

• molecule, yielding BMN as the final product (Scheme 1B) [49]. In the initial trial, 12 mol % of the MOF catalyst was added to a vial containing benzaldehyde, malononitrile, toluene as solvent, and dodecane as internal standard, and the reaction was shaken at 50 °C. Aliquots were collected at 30 minutes

Synthesis of optically active folded cyclic dimers and trimers

• Ena Kumamoto,
• Kana Ogawa,
• Kazunori Okamoto and
• Yasuhiro Morisaki

Beilstein J. Org. Chem. 2025, 21, 1603–1612, doi:10.3762/bjoc.21.124

• and tuning mix as internal standard or on a JEOL JMS-S3000 spectrometer for matrix-assisted desorption/ionization (MALDI) with trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB) as a matrix. UV–vis absorption spectra were recorded on a JASCO V-730 spectrophotometer, and

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• different substituents, including aryl, heteroaryl, and alkyl groups at the terminal alkyne, were well tolerated, yielding moderate to good results (16aa–da). Furthermore, variations in the nitrile reaction partners, such as butyronitrile (16ea), 2-phenylacetonitrile (16fa), malononitrile (16ga), and 3-oxo

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• asymmetric allylic amination of allylic esters with isatin derivatives 11 as nucleophiles. The reaction proceeds efficiently, yielding the products (S)-13 with good-to-high enantioselectivity. A scale-up reaction was also successfully conducted at a 1 mmol scale. Additionally, when malononitrile was added to

• the resulting product (S)-13a in the presence of FeCl3 as the catalyst, the corresponding malononitrile derivative (S)-16 was obtained without any loss in optical purity. Keywords: asymmetric allylic amination; axial chirality; isatin; palladium catalysis; P,olefin-type chiral ligand; Introduction

• applications of this product, we treated (S)-13a (94% ee) with malononitrile in the presence of FeCl3 as a catalyst [36] and obtained the corresponding malononitrile derivative (S)-16 without any loss of optical purity (Scheme 3). Conclusion In this study, N-propyl-N-cinnamoylamide 7 was synthesized in three

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

• in the final product 37 (Scheme 28) [46]. Analogously, benzo[g]chromene derivatives 38 were achieved starting from 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and malononitrile with copper triflate as catalyst and ultrasonic irradiation (Scheme 29) [47]. Naphthalene-annulated 2-aminothiazoles

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

• ) 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

• efficient methodology for synthesizing chiral benzofuran-fused 1,4-dihydropyridines 13 in excellent yields (90–99%) and excellent enantioselectivities (92–99% ee) (Scheme 4). The authors also attempted to perform the reaction using 2-tosylacetonitrile instead of malononitrile. However, in this case, the

• Michael addition product was obtained with low diastereoselectivity. The mechanism is described in Scheme 4: the bifunctional squaramide activates the azadiene through hydrogen bonding while the malononitrile is deprotonated by the tertiary amine present in the backbone of the catalyst, establishing

The charge transport properties of dicyanomethylene-functionalised violanthrone derivatives

• Sondos A. J. Almahmoud,
• Joseph Cameron,
• Dylan Wilkinson,
• Michele Cariello,
• Claire Wilson,
• Alan A. Wiles,
• Peter J. Skabara and
• Graeme Cooke

Beilstein J. Org. Chem. 2024, 20, 2921–2930, doi:10.3762/bjoc.20.244

• the Knoevenagel condensation with malononitrile was successfully reported [33]. Theoretical studies Density functional theory (DFT) calculations of two derivatives of compounds 2 and 3, having methoxy groups instead of the longer alkyl chains have been reported in the literature [32], providing

• , 127.5, 127.2, 123.7, 123.2, 122.8, 117.3, 113.6, 69.8, 63.2, 32.9, 32.0, 29.7, 29.6, 29.5, 29.4, 26.2, 25.8 , 22.8, 14.2; ASAP–HRMS (m/z): [M + H]+ calcd for C58H64O4, 825.4875; found, 825.4883. Compound 3a Compound 2a (200 mg, 0.280 mmol) and malononitrile (100 mg, 0.840 mmol) were dissolved in

• , 129.6, 128.6, 128.3, 127.9, 127.7, 127.3, 123.9, 123.3, 122.9, 117.6, 114.6, 65.5, 42.1, 40.1, 30.2, 29.2, 23.2 (C, 14.2, 11.2; ASAP–HRMS (m/z): [M + H]+ calcd for C56H49N4O2, 809.3841; found, 809.3856 . Compound 3b Compound 2b (200 mg, 0.28 mmol) and malononitrile (60.0 mg, 0.840 mmol) were dissolved

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• electrophilic sites simultaneously in their structure, these zwitterions are able to participate in various cyclization processes, especially for the synthesis of pyrroles [37][38][39][40]. For example, Li et al. developed a one-pot four-component reaction (4-CR) of malononitrile, aldehydes, and isocyanides

• with 1,10-phenanthroline as cyclic imine under solvent-free conditions for the synthesis of pyrrole-fused phenanthroline. This reaction proceeds via in situ formation of zwitterion I through reaction of the aldehyde and malononitrile followed by 1,3-dipolar cycloaddition (Scheme 1a) [41]. Chen and co

• benzoxazepine/triazolobenzodiazepine derivatives via a 3-CR prompted us to investigate the synthesis of these compounds as a 4-CR. Fortunately, the pyrrole-fused benzoxazepine/triazolobenzodiazepines 4a and 6a could also be obtianed through a one-pot 4-CR from benzaldehyde, malononitrile, cyclohexyl isocyanide

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

• method to access structurally diverse chiral coumarin derivatives, which are of great interest in the fields of medicinal chemistry and synthetic organic chemistry (Scheme 22, 22a–y). Moreover, the utilization of 2-(1-ethoxyethylidene)malononitrile as a γ-nucleophile yielded the desired product 22z with

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

• , and stereochemistry of the major isomer was deduced from the above result as anti,syn. Although malononitrile also furnished the dihydrofuran syn-7d in good yield as a sole stereoisomer, a sharp contrast to these results was observed when 2b was subjected to the anionic species from cyanoacetate

• of the active hydrogen in DMSO: 13.3 [52]), nitromethane (17.2 [53]), ethyl (diethylphosphono)acetate (18.6 [52]), malononitrile (11.1 [53]), ethyl 2-nitroacetate (9.1 [54]), ethyl 2-cyanoacetate (13.1 [55]), and diethyl malonate (16.4 [56]) all failed to afford the desired addition products. From

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• pyrazoles 61 are accessible in a consecutive three-component fashion (Scheme 18) [77]. The reaction exhibits regioselectivity in many cases, attributed to steric influences. Aldehydes and nitriles with an activated methylene group, such as malononitrile, are well-known for being potent precursors of α,β

• base in the Knoevenagel reaction and as a component for ring formation. Cyclization is completely regioselective when arylhydrazines are used; with methylhydrazine, the ratio is greater than 10:1. In addition to malononitrile, derivatives with reduced nucleophilicity (X = CO2R) are also tolerated in

• hydrolactite catalysts (C-Mg-Al HAT-3) [90]. With β-ketoesters, the method can be extended to a four-component synthesis. Initially, β-ketoesters react with hydrazine to form pyrazolones, while a Knoevenagel reaction between malononitrile and aldehyde simultaneously generates a Michael system. Both

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• synthesize functionalized pyrimidobenzothiazoles [37]. An in situ generated conjugated α-cyanoester/malononitrile has been successfully employed as substrate in the double Michael reaction with curcumins by Lalitha et al. [38]. An organocatalytic cascade double Michael reaction between curcumins and 2

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

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• the starting material. This compound was prepared according to the described regioselective method [42] based on the reaction of malononitrile with triethyl orthoformate followed by subsequent treatment of the obtained dinitrile 2 with benzaldehyde methyl hydrazone in benzene, conc. aqueous HCl in

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• Orbitrap XL equipped with nitrogen UV laser (337 nm, 60 Hz, 8–20 μJ) in positive ion mode. For the CID experiment using the linear trap quadrupole (LTQ) helium was used as the collision gas and 2,5-dihydroxybenzoic acid (DHB) or (2-methylprop-2-en-1-yliden)malononitrile (DCTB) as the MALDI matrix

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• to be a 1:1:1 ratio of 2-unsubstituted imidazole N-oxides as C-nucleophile, ethyl cyanoacetate as C–H acidic electrophile and 4-(methylsulfanyl)benzaldehyde as aldehyde catalyst, DMF as solvent at 100 °C for 5 h. Under the optimized conditions, malononitrile providing the products 4i,j (36–45%), 2

Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates

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

Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99

• , phenacylmalononitrile is also a readily available substrate, which can be easily prepared through a base-promoted substitution reaction of phenacyl bromide with malononitrile under mild conditions [11][12][13][14][15][16]. In many practical cases, phenacylmalononitriles could be conveniently generated in situ by

• directly using a mixture of phenacyl bromide and malononitrile in the reaction system [17][18][19][20][21][22]. As a consequence, the unique features of phenacylmalononitriles make them good candidates for the efficient construction of diverse carbocyclic and heterocyclic compounds [23][24][25][26][27][28

• reaction of phenacyl bromide, malononitrile, dialkyl but-2-ynedioate, and triphenylphosphine has been already reported, in which diethyl 3-phenyl-5,5-dicyanocyclopent-2-ene-1,2-dicarboxylates were produced by further elimination of a hydroxy group [30]. In the present reaction, the hydroxy group is still

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

• applied in such catalytic system. Under the same reaction conditions, the three-component reaction of 2-methylindole, benzaldehyde and 2-(1-benzyl-2-oxoindolin-3-ylidene)malononitrile reacted smoothly to give the expected spiro[carbazole-2,3'indolines] in 51% yield with a diastereometric ratio (dr) value

• cycloaddition between the indole-based ortho-quinodimethanes (o-QDMs, A) and dienophiles affords the final spiro compounds 1, 2, 4 and 5 as major isomers through an endo-transition state. Due to the different polarity, 3-phenacylideneoxindole and isatylidene malononitrile resulted in regioisomeric spiro

• procedure for the preparation of the spiro[carbazole-2,3'-indolines] 2a–g and 2a’–g’: A mixture of 2-methyl-1H-indole (0.5 mmol, 1.0 equiv), aldehyde (0.6 mmol, 1.2 equiv), 2-(1-benzyl-2-oxoindolin-3-ylidene)malononitrile (0.5 mmol, 1.0 equiv) and CuSO4 (0.1 mmol, 0.2 equiv) in dry toluene (6.0 mL) was

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

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

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• functionalized various spiro[cyclohexane-1,3'-indolines] and related reactions. Results and Discussion Initially, the reaction conditions were optimized by using isatylidene malononitrile 1a and bis-chalcone 2a as standard reaction. Tertiary amines such as DMAP and DABCO did not catalyze this reaction (entries 1

• this work. Firstly, the nucleophilic addition of tributylphosphine to the bis-chalcone gives the active zwitterionic species (A). Secondly, the Michael addition of the zwitterionic species (A) to isatylidene malononitrile at the C3-position of the oxindole scaffold results in adduct (B). Thirdly, the

• of the zwitterion A to the isatylidene malononitrile 2 and 3-(ethoxycarbonylmethylene)oxindole 4 results in the different regioselectivity in the formation of the spiro compounds 3 and 5. For further demonstrate the synthetic value of this procedure, ethyl isatylidene cyanoacetates 6 were also

Synthesis of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines and investigation of their fungistatic activity

• Anna V. Korotina,
• Svetlana G. Tolshchina,
• Rashida I. Ishmetova,
• Natalya P. Evstigneeva,
• Natalya A. Gerasimova,
• Natalya V. Zilberberg,
• Nikolay V. Kungurov,
• Gennady L. Rusinov,
• Oleg N. Chupakhin and
• Valery N. Charushin

Beilstein J. Org. Chem. 2022, 18, 243–250, doi:10.3762/bjoc.18.29

• modify the triazolo[1,5-b][1,2,4,5]tetrazine ring system with a variety of structural fragments, thus enabling to vary their biological activity. The reactions of new triazolo[1,5-b][1,2,4,5]tetrazines with some CH-active compounds, such as malononitrile, ethyl cyanoacetate and diethyl malonate, have

• triazolotetrazepines [36]. At the same time, a more active malononitrile reacts easily with compounds 3a,j to afford triazolopyrimidines 6a,b (Scheme 4). In the reaction of ethyl cyanoacetate with triazolotetrazine 3j, a mixture of products is formed, in which, along with the diamino compound 7 and triazolotetrazepine

Solvent-free synthesis of enantioenriched β-silyl nitroalkanes under organocatalytic conditions

• Akhil K. Dubey and
• Raghunath Chowdhury

Beilstein J. Org. Chem. 2021, 17, 2642–2649, doi:10.3762/bjoc.17.177

• % ee). The conjugate addition reaction between malononitrile and β-silylenone 1a was also investigated using 5 mol % of catalyst VII under the optimized reaction conditions. To our delight, the reaction completed within 4 h and the desired product 3m was isolated in excellent yield (97%) with moderate

Towards new NIR dyes for free radical photopolymerization processes

• Haifaa Mokbel,
• Guillaume Noirbent,
• Didier Gigmes,
• Frédéric Dumur and
• Jacques Lalevée

Beilstein J. Org. Chem. 2021, 17, 2067–2076, doi:10.3762/bjoc.17.133

• asymmetric substitution. Thus, in the first step, the Claisen–Schmidt condensation of 2-chloro-3-(hydroxymethylene)cyclohex-1-ene-1-carbaldehyde on 2-(3-cyano-4,5,5-trimethylfuran-2(5H)-ylidene)malononitrile (TCF) furnished the intermediate 2-(4-((E)-2-((E)-2-chloro-3-(ethoxymethylene)cyclohex-1-en-1-yl

• )vinyl)-3-cyano-5,5-dimethylfuran-2(5H)-ylidene)malononitrile in 65% yield. A second Claisen–Schmidt condensation of 2-(4-((E)-2-((E)-2-chloro-3-(ethoxymethylene)cyclohex-1-en-1-yl)vinyl)-3-cyano-5,5-dimethylfuran-2(5H)-ylidene)malononitrile with the appropriate 3-alkyl-1,1,2-trimethyl-1H-benzo[e]indol-3