Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• each on the pyridine ring. Moreover, IPs with a non-aromatic C-2 substituent like an ester group were also included (4r). We also explored bromo analogues of other active methylenes such as ethyl cyanoacetate, ethyl acetoacetate, dimethyl, and diisopropyl malonates, as extension of diethyl malonate (4s

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• cyclization. The chiral starting material was prepared by an asymmetric Cu-catalyzed tandem conjugate addition/acylation sequence using ethyl cyanoacetate (Mander’s reagent) as a trapping agent (Scheme 56A). Activation of the zinc enolate by MeLi was necessary, but with optimum reaction conditions the authors

• addition to cyclohexenone 1, followed by the trapping of the Mg enolate with ethyl cyanoacetate (221). Consequent α-alkylation resulted in the multifunctionalized product 223 in 61% yield (Scheme 58). Natural products with complex multicyclic structures lacking functional groups (lack of oxygenation) are

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

• -[(4-chlorophenyl)sulfonyl]acetonitrile gave the corresponding products 4k,l (18–51%) and 2-tosylacetonitrile producing the expected product 4h (28%) can also act as the C–H acids in place of ethyl cyanoacetate. But the yields of the products were relatively low. Here, the product 4c was obtained only

• , the authors revealed the product 4a as E-isomer due to the strong intramolecular H-bonding. It was also observed that the labile acetal group in the product 4g remained unaffected during the reaction process under the standard conditions. Imidazole N-oxides reacted with ethyl cyanoacetate to produce

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

• reaction of 7-methyl-substituted triazolotetrazine 3a with ethyl cyanoacetate, a rather complicated mixture of several products has been obtained, none of the latter failed to be isolated in a pure form. Thus, it has been shown that new triazolo[1,5-b][1,2,4,5]tetrazines retain electrophilic centers

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

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

• -catalyzed three-component reaction between aromatic aldehydes 5, ethyl cyanoacetate (73) (active methylene group) and benzamidine (74) in aqueous media for the construction of substituted pyrimidinones 75 under microwave irradiation (Scheme 26). The study of the protocol on a conventional system directed a

• proposed two different mechanisms in which the first mechanism involved two subsequent reactions. The first one being a Knoevenagel condensation between aromatic aldehyde and ethyl cyanoacetate to yield a Knoevenagel intermediate A which upon subsequent reaction with benzamidine, forms Michael adduct B. A

• between aldehyde and amidine. The imine G thereby reacts with ethyl cyanoacetate to result in intermediate I, which on intramolecular cyclization leads to D. The remaining pathway pursues same mechanism as the first one (Scheme 27). Later in 2016, Gopalakrishnan and co-workers [74] demonstrated the

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

• transformation into a C–C bond. Compounds containing electron-withdrawing groups such as malonitrile, dimedone, ethyl cyanoacetate and diethyl malonate were used as C-nucleophiles. Transformations were performed in DMF in the presence of NaH and the products were obtained in high yields (Scheme 6). The lower

• 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

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

• Ksenia I. Kaskevich,
• Anastasia A. Babushkina,
• Vladislav V. Gurzhiy,
• Dmitrij M. Egorov,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2020, 16, 1947–1954, doi:10.3762/bjoc.16.161

• ], anti-inflammatory [8][9], and antiviral [10][11]. The best known methods for the preparation of thiazolopyrimidines are based on condensation reactions. The most commonly used synthesis is the three-component condensation of 2-aminothiazoline, aromatic aldehyde, and ethyl cyanoacetate, which leads to

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• Strukturchemie, Universitätsstraße 1, D-40225 Düsseldorf, Germany 10.3762/bjoc.15.262 Abstract Starting from substituted alkynones, α-pyrones and/or 1H-pyridines were generated in a Michael addition–cyclocondensation with ethyl cyanoacetate. The peculiar product formation depends on the reaction conditions as

• by cyclocondensation with ketene dithioacetals and substituted acetophenones other cyano-containing derivatives became accessible by desymmetrizing cyclocondensation of 1,2-diaroylacetylenes with ethyl cyanoacetate [27], similar to related studies with dialkyl malonates [28]. Here, we report on

• ), phenylacetylene (2a), and ethyl cyanoacetate (4) within the AMAC sequence (Scheme 2). Surprisingly, the desired α-pyrone was not isolated, but two other compounds were detected. On the one hand a 1H-pyridine derivative 5a (2% yield) and on the other hand an aniline derivative with two ester groups (4% yield

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• -aminopyrazole 16 with aldehydes 47 and ethyl cyanoacetate (94) in ethanol in presence of p-toluenesulfonic acid which resulted in a diastereomeric mixture of cis- and trans-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridines 95. Benzaldehydes 47 with electron withdrawing groups provided better yields of the cis

• reported a similar reaction of 5-aminopyrazole 16, arylaldehyde 47 with ethyl cyanoacetate (94) under ultrasound irradiation in presence of p-TSA in water for the synthesis of 3-methyl-6-oxo-4-aryl-4,5,6,7-tetrahydro-4H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives 95 (Scheme 27). All the synthesized

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• . Results and Discussion In order to generate the core indole unit through a robust synthetic sequence we decided to investigate the treatment of a 2-chloronitrobenzene 9 with ethyl cyanoacetate (10) as the nucleophile in a base-mediated SNAr reaction (Scheme 1). The resulting adduct 11 would then be

• substrate 9 to be processed with TMG or DBU (2.5 equiv) and ethyl cyanoacetate (10, 1.1 equiv) at 50 °C in quantitative conversion. Based upon these screening results we devised a simple flow set-up where two stock solutions were united at a simple T-mixing piece and subsequently directed into a heated flow

• base and the ethyl cyanoacetate (10) being combined (note this was an exothermic process) before meeting a solution of the aryl chloride 9 and entering the ACR which was agitated at 8 Hz (Scheme 3). In an attempt to intensify the process and with the specific aim of reducing the amount of solvent in

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• cyanoacetates as well as their bromo and dibromo derivatives are the most important starting materials. The first described method comprised the treatment of ethyl cyanoacetate (2a) with SeO2 at 120–125 °C, leading to E-1a in ca. 10% yield [4] (Scheme 1). More efficient syntheses of diverse dialkyl esters E-1

The reactions of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole as a way to novel azaheterocycles

• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess and
• Viktor I. Saloutin

Beilstein J. Org. Chem. 2015, 11, 385–391, doi:10.3762/bjoc.11.44

• [М]+) (Scheme 5). It can be assumed that ethyl cyanoacetate (12), formed as a result of ethoxymethylidene group migration to 5-AT, reacts with ester 1f to give intermediate diester 14 (Scheme 5). The latter is cyclised with 5-AT into pyridine 11 via intermediates H and I. We carried out the three

One-pot four-component reaction for convenient synthesis of functionalized 1-benzamidospiro[indoline-3,4'-pyridines]

• Chao Wang,
• Yan-Hong Jiang and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2014, 10, 2671–2676, doi:10.3762/bjoc.10.281

• -substituted spiro[indoline-3,4’-pyridine]. It should be noted that pure products can be obtained by washing the formed precipitates from the reaction solution and no further purification process is needed. The similar reactions with ethyl cyanoacetate also produced the spiro compounds 1e–i in 68–74% (Table 1

• acetylenedicarboxylate results in an active zwitterionic intermediate (A). In the meantime, the condensation of isatin with malononitrile or ethyl cyanoacetate in the presence of triethylamine affords isatylidenemalononitrile or its derivative (B). Then the nucleophilic addition of the zwitterionic intermediate (A) to

• four-component reaction. Conclusion In summary, we have investigated the four-component reactions of benzohydrazide, acetylenedicarboxylate, isatins and malononitrile or ethyl cyanoacetate and successfully developed an efficient synthetic procedure for the preparation of functionalized 1-benzamidospiro

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• [1,2-b]pyrazole library in sequential one-pot protocol utilizing four components such as hydrazine hydrate, ethoxymethylene substituted malononitrile or ethyl cyanoacetate derivatives, isocyanides and aldehydes. Results and Discussion In the initial stage, a model GBB-3CR was performed between 5

Synthesis of functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] via one-pot four-component reactions

• Li-Juan Zhang,
• Qun Wu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 846–851, doi:10.3762/bjoc.9.97

• malononitrile afforded the functionalized spiro[indoline-3,4’-pyridine] derivatives in good yields. Similar reactions with ethyl cyanoacetate successfully afforded the functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] as the main products according to the structures of the

• reactions of arylamines, methyl propiolate, aromatic aldehydes and malononitrile (ethyl cyanoacetate) and successfully developed a facile synthetic procedure for functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones]. Results and Discussion The efficient formation of

• structures of the prepared spiro[indoline-3,4’-pyridines] 1a–1p were fully characterized by spectroscopic methods and were further confirmed by the determination of the single crystal structures of the spiro compounds 1c (Figure 1) and 1h (Figure 2). When ethyl cyanoacetate was utilized in the domino

Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities

• Hany M. Mohamed,
• Ashraf H. F. Abd EL-Wahab,
• Ahmed M. EL-Agrody,
• Ahmed H. Bedair,
• Fathy A. Eid,
• Mostafa M. Khafagy and
• Kamal A. Abd-EL-Rehem

Beilstein J. Org. Chem. 2011, 7, 1688–1696, doi:10.3762/bjoc.7.199

• ethyl 6,8-diiodocoumarin-3-carboxylate (1) with ethyl cyanoacetate/NH4OAc gave ethyl 2-(3-carbamoyl-6,8-diiodocoumarin-4-yl)-2-cyanoacetate (12) and 2-amino-4-hydroxy-7,9-diiodocoumarino[3,4-c]pyridine-1-carbonitrile (13), and treatment with acetone in the presence of NH4OAc or methylamine gave the

• -diiodosalicylaldehyde; diethyl malonate; ethyl cyanoacetate; coumarins; Michael reaction; Introduction Coumarins and their derivatives are biologically and pharmaceutically interesting compounds known for their use as additives in food, perfumes, cosmetics, pharmaceuticals, platelet aggregation and agrochemicals [1][2

• -withdrawing carbonyl groups, the behavior of 1 towards activated methylene compounds under Michael reaction conditions was investigated. Thus, treatment of 1 with ethyl cyanoacetate/NH4OAc in boiling ethanol afforded two reaction products. The insoluble reaction product was identified as ethyl 2-(3-carbamoyl

C–C (alkynylation) vs C–O (ether) bond formation under Pd/C–Cu catalysis: synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines

• Dhilli Rao Gorja,
• K. Shiva Kumar,
• K. Mukkanti and
• Manojit Pal

Beilstein J. Org. Chem. 2011, 7, 338–345, doi:10.3762/bjoc.7.44

• -tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidine (1d) was prepared from cycloheptanone and ethyl cyanoacetate following a similar procedure as shown in Scheme 2. Condensation of resulting amino ester, i.e., ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (4) with formamide gave

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• -aryl-4-(benzothiazol-2-yl)pyrazoles 131 (Scheme 35) [77]. Similarly, hydrazonyl chloride 132 on treatment with ethyl cyanoacetate in NaH/DMF at 0 °C gave intermediate 133 which underwent cyclization to afford 5-amino-4-carbethoxy-3-methyl-1-(4-sulfamoylphenyl)pyrazole 134 (Scheme 36) [78]. The

• in the presence of base to yield the desired compounds 162 (Scheme 46). Abdelhamid et al. [89][90] have reported the synthesis of substituted 5-aminopyrazoles 164 by the treatment of active methylene compounds such as malononitrile, ethyl cyanoacetate etc. with hydrazonoyl halides 163 in ethanolic

A new and facile synthetic approach to substituted 2-thioxoquinazolin-4-ones by the annulation of a pyrimidine derivative

• Nimalini D. Moirangthem and
• Warjeet S. Laitonjam

Beilstein J. Org. Chem. 2010, 6, 1056–1060, doi:10.3762/bjoc.6.120

• derivatives of 1,3-diarylthiobarbituric acids (DTBA) with active methylene compounds, such as malononitrile and ethyl cyanoacetate, in presence of ZnCl2 has been developed. Keywords: benzenoid; ethylcyanoacetate; malononitrile; pyrimidine; 2-thioxoquinazolin-4-ones; Introduction Quinazolines and derivatives

• system, resulted in a new method for the formation of quinazoline derivatives. Thus, the reaction of 5-ethoxymethylenepyrimidine-4,6-diones 1 with malononitrile and ethyl cyanoacetate gave 7-amino-2,3-dihydro-2-thioxo-1,3-diarylquinazolin-4(1H)-ones 2 and 7-hydroxy-2,3-dihydro-2-thioxo-1,3

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

• Arumugam Kodimuthali,
• Padala Lakshmi Prasunamba and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71

• ], antibacterial agents [12][13][14][15], Janus kinase 3 (JAK3) inhibitors [16], Calcitonin-Gene Related Peptide (CGRP) modulators [17] etc. Our synthesis of compound 9 (R = Boc) is shown in Scheme 1. Commercially available ethyl cyanoacetate and 1,2-dibromoethane was used to construct the appropriately

Hydroxyapatite supported caesium carbonate as a new recyclable solid base catalyst for the Knoevenagel condensation in water

• Monika Gupta,
• Rajive Gupta and
• Medha Anand

Beilstein J. Org. Chem. 2009, 5, No. 68, doi:10.3762/bjoc.5.68

• Monika Gupta Rajive Gupta Medha Anand Department of Chemistry, University of Jammu, Jammu 180 006, India 10.3762/bjoc.5.68 Abstract The Knoevenagel condensation between aromatic aldehydes and malononitrile, ethyl cyanoacetate or malonic acid with hydroxyapatite supported caesium carbonate in

• water is described. HAP–Cs2CO3 was found to be a highly active, stable and recyclable catalyst under the reaction conditions. Keywords: ethyl cyanoacetate; hydroxyapatite supported caesium carbonate; Knoevenagel condensation; malonic acid; malononitrile; Introduction An area of recent intense

• primarily used in the synthesis of fine chemicals in agriculture and medicine and as precursors of heterocycles with biological activity [8][9][10][11][12][13][14][15][16] whilst arylidene derivatives of ethyl cyanoacetate are successfully employed in the synthesis of cyanocoumarins [17][18], as

An expedient and new synthesis of pyrrolo[1,2-b]pyridazine derivatives

• Rajeshwar Reddy Sagyam,
• Ravinder Buchikonda,
• Jaya Prakash Pitta,
• Himabindu Vurimidi,
• Pratap Reddy Padi and
• Mahesh Reddy Ghanta

Beilstein J. Org. Chem. 2009, 5, No. 66, doi:10.3762/bjoc.5.66

• condensation reactions, such as the condensation of oxazolo[3,2-b]pyridazinium perchlorates with malononitrile, ethyl cyanoacetate and ethyl malonate in the presence of sodium ethoxide [15]; the condensation of 1,4,7-triketones with hydrazine followed by dehydrogenation [16]; the condensation of cyanoacetic

An easy synthesis of 5-functionally substituted ethyl 4-amino- 1-aryl- pyrazolo- 3-carboxylates: interesting precursors to sildenafil analogues

• Said A. S. Ghozlan,
• Khadija O. Badahdah and
• Ismail A. Abdelhamid

Beilstein J. Org. Chem. 2007, 3, No. 15, doi:10.1186/1860-5397-3-15

• report results of our work aimed at exploring this synthetic methodology and adoption of products for the synthesis of pyrazolo[4.3-d]pyrimidines. Thus, compounds 1a-c, were prepared according to literature procedures via coupling of ethyl cyanoacetate with aromatic diazonium salts [10]. It has been