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

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• proved to be less active. In 2013, the Knoevenagel reaction between benzaldehyde (17) and malononitrile was performed using a similar flow apparatus, however, using a polystyrene-supported DABCO as catalyst. Wang’s group confirmed the stability of the latter, which provides excellent conversions (95–90

Structural effects of meso-halogenation on porphyrins

• Keith J. Flanagan,
• Maximilian Paradiz Dominguez,
• Zoi Melissari,
• Hans-Georg Eckhardt,
• René M. Williams,
• Dáire Gibbons,
• Caroline Prior,
• Gemma M. Locke,
• Alina Meindl,
• Aoife A. Ryan and
• Mathias O. Senge

Beilstein J. Org. Chem. 2021, 17, 1149–1170, doi:10.3762/bjoc.17.88

• quadrupole time-of-flight (Q-TOF) mass spectrometer equipped with Z-spray electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) sources either in a positive or negative mode with DCTB (trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile) as the matrix. UV

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• ]. Therefore, researchers have quested upon generation of pyrans and benzopyrans employing MCR powered by microwave assistance. For instance, Tu and co-workers [55] reported a one-pot two-step tandem procedure subjecting phenylenediamine 23, 2-hydroxynaphthalene-1,4-diones (11), aldehyde 5 with malononitrile

• diamine 23 and 2-hydroxynaphthalene-1,4-dione (11). A simultaneous condensation between malononitrile and aldehyde afforded 2-benzylidenemalononitrile B which on Michael addition with condensed intermediate A yields intermediate C, to undergo cyclization and resulted in the desired products (52, Scheme 18

• ). The synthesis of indoline-spiro fused pyran derivatives 53 was reported by Jiang and co-workers [57] employing a multicomponent reaction between substituted isatins 35, cyclic 1,3-diketones 6 and malononitrile (51) in an aqueous medium without any catalyst. Reaction diversity was examined by using

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• heating, or photochemically in a nitrogen atmosphere (Scheme 23) [109]. The reaction of spiro[10-anthron-9,61'-methanofullerene] (79) [110] with bis(trimethylsilyl)carbodiimide and malononitrile in pyridine in the presence of TiCl4 resulted in spirocyclic blocks 80 and 81, respectively (Scheme 24) [111

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

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

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• acid (DHB) or (2-methylprop-2-en-1-yliden)malononitrile (DCTB) as the MALDI matrix. Elemental analyses were performed on a Flash 2000 Organic Elemental Analyser (Thermofisher). For samples containing chlorine mercurimetric titration was used. IR spectra were recorded on a Nicolet iS50 equipped with an

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• 2205 cm−1 for product 5c. These results differ from the absorption in the range of 2260–2240 cm−1, which would be characteristic for a cyano group attached to sp3-hybridized carbon [82]. On the other hand, 13C NMR shifts of the C(2’’) position of purine–malononitrile conjugate 5a and ethyl cyanoacetate

• -1-yl)-1,9-dihydro-6H-purin-6-ylidene)malononitrile (5a): Under argon atmosphere to a suspension of 9-heptyl-2,6-bis(4-phenyl-1H-1,2,3-triazol-1-yl)-9H-purine (2c, 141 mg, 0.28 mmol, 1 equiv) in anhydrous DMF (2.5 mL) malononitrile (23 mg, 0.35 mmol, 1.3 equiv) and NaH (8 mg, 0.34 mmol, 1.2 equiv

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• was discussed previously [29]. The reaction of 4 with malononitrile-derived gem-dithiolate (5b, Scheme 1, route 2) also proceeded under mild conditions in DMF and bicyclic o-quinone 6b was obtained in a good yield. The brown crystals suitable for X-ray analysis were grown from an acetone/diethyl ether

• mixture. X-ray diffraction data revealed that the bond lengths distribution in the six-membered ring of 6b is typical of sterically hindered o-quinones. The annulated fragment including the 1,3-dithiole cycle and the malononitrile unit is almost flat. The six-membered o-quinone ring is distorted due to

• phase. In order to attach the 1,3-diketonate moiety to the periphery of the o-quinone molecule, we treated the o-quinone 4 with sodium gem-dithiolate obtained from acetylacetone (5d, Scheme 1, route 2). Unlike interactions with sodium trithiocarbonate or malononitrile gem-dithiolate, the o-quinone 6d

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• malononitrile under catalyst-free conditions have been reported [29]. Wang et al. reported the functionalization of benzylic C–H bonds of 2-methylazaarenes by nucleophilic addition to aromatic aldehydes catalyzed by acetic acid using harmful chlorinated solvent, and this reaction suffers from longer reaction

Styryl-based new organic chromophores bearing free amino and azomethine groups: synthesis, photophysical, NLO, and thermal properties

• Anka Utama Putra,
• Deniz Çakmaz,
• Nurgül Seferoğlu,
• Alberto Barsella and
• Zeynel Seferoğlu

Beilstein J. Org. Chem. 2020, 16, 2282–2296, doi:10.3762/bjoc.16.189

• employed to gain insight into the experimental data. Results and Discussion Synthesis As depicted in Scheme 1, dye 2 was obtained in good yield by reacting malononitrile and 4-aminoacetophenone (compound 1) according to our previous published procedure [31][32]. The styryl-based organic chromophores 3–7

• 2 was published previously [31][32]. Dyes 3–7 were synthesized using 2 and the appropriate benzaldehyde. Equimolar (3 mmol) amounts of 2-(1-(4-aminophenyl)ethylidene)malononitrile (2) and the appropriate benzaldehyde derivative in 20 mL of ethanol were refluxed for 2 h. A colored solid formed for

• all dyes 3–7 which was collected by filtration and recrystallized from ethanol to obtain the pure dyes. ((E)-2-(1-(4-Aminophenyl)-3-(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)allylidene)malononitrile) (3) Dark purple solid; yield: 64%; mp 236–238 °C; FTIR (cm−1): 3441, 3349, 3224, 2920

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

• Kumar Godugu,
• Venkata Divya Sri Yadala,
• Mohammad Khaja Mohinuddin Pinjari,
• Trivikram Reddy Gundala,
• Lakshmi Reddy Sanapareddy and
• Chinna Gangi Reddy Nallagondu

Beilstein J. Org. Chem. 2020, 16, 1881–1900, doi:10.3762/bjoc.16.156

• -ranging biological activities [62][63]. The most common synthetic route for the preparation of 2-amino-4-aryl-3,5-dicarbonitrile-6-thiopyridines is the condensation reaction of aldehydes, malononitrile, and thiols in the presence of a variety of catalysts [64][65][66][67][68][69][70][71][72]. Though the

• purpose, a control experiment in the absence of a catalyst was conducted by using the model substrates benzaldehyde (2a, 1.0 mmol), malononitrile (8, 2.0 mmol), and 2-mercaptopyridine (9, 1.0 mmol) in H2O (3.0 mL) under ultrasound irradiation at 45–50 °C for 60 min. It was observed that the reaction did

• was increased from 30 to 40 min. The optimized procedure was successfully applied for the synthesis of a series of highly substituted pyridines (11b–r, Table 7) by utilizing a range of (hetero)aromatic aldehydes 2, malononitrile (8), and the thiols 9 and 10, respectively, as starting materials

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• ). Alkyl-substituted derivatives proved to be similarly successful substrates; however, the TMS-substituted derivative was obtained in a significantly lower yield. In terms of linkers, heteroatoms were well-tolerated, although the use of malononitrile resulted exclusively in the elimination product despite

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• epoxidation agent of an electron-deficient olefin intermediate, which was formed by deaminative Mannich coupling between the imine and nucleophiles such as malononitrile and methyl cyanoacetate (Scheme 64) [109]. Overall, a variety of additional examples of porphyrin-photocatalyzed heteroatom oxidations are

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• -indanedione (2c), malononitrile (2e), 4-cyanomethyl-2,3,5,6-tetrafluorobenzonitrile (2f) were successfully applied as active methylene compounds; all of them have pKa values between 4.70 (2b, in dioxane/H2O 3:1 [20]) and ≈15.80, reported for 2-(pentafluorophenyl)acetonitrile in DMSO [21], the value for 2f

• , which reacted with PPh3 and malononitrile to furnish the desilylated betaine E-3o; the required proton probably stems from the adventitious presence of water (Scheme 4). Notably, 3o could not be obtained directly from the 3-H substituted N-triflylpropiolamide 1g. Some betaines 3 were isolated solely as

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• androstanic steroids. Such heterocyclic moieties are of interest because of their pharmacological activity, for example, as anti-inflammatory agents. Employing epiandrosterone and benzaldehyde as oxo components, ammonium acetate and malononitrile as C-nucleophile, the authors produced 2-amino-3-cyano-1,4

• -dihydropyridine 46 fused to the androstane at positions 16 and 17 (Scheme 14). The MCR proceeds by the condensation of malononitrile with benzaldehyde to form the benzylidene malononitrile adduct, and of the ketosteroid with ammonium to form the steroidal enamine, which cyclizes with the benzylidene to furnish

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• acyclic CH acids. As the last compounds we have used Meldrum’s acid, malononitrile and ethyl 2-cyanoacetate. Results and Discussion In view of the structure of 2-amino-4-arylimidazoles containing four nonequivalent nucleophilic centres several pathways can be assumed for their reactions with carbonyl 1,3

• active compounds, that can lead to cyclic products, has a high potential for diversity-oriented synthesis. In the three-component condensations of equimolar amounts of 2-amino-4-arylimidazoles 1, para-substituted benzaldehydes 2 and malononitrile (12) in 2-propanol the Knoevenagel–Michael adduct was not

• -arylimidazole 1 (1.0 mmol), aromatic aldehyde 2 (2.0 mmol) and malononitrile 12 (1.0 mmol) in 2 mL of 2-propanol was refluxed during 20–30 min. After cooling, the yellow solid products 14 were filtered off and crystallized from iPrOH. 14a: yellow powder, 65%; mp 221–222 °C; 1H NMR (200 MHz, DMSO-d6) δ 9.34 (s