Cyanoacetic Ester Research Articles

The Craven reaction with 2-aryl-1,4-benzoquinones

It is known that the interaction of 1,4-quinones with 1,3-dicarbonyl compounds mainly results in the formation of benzo[ b ]furan derivatives, which attract special attention because many compounds of this class are biologically active and are used as drugs. However, in some cases, this interaction is ambiguous, and along with the main reaction products – substituted benzofurans, significant amounts of benzodifurans are formed. Cyanoacetic acid derivatives are particularly prone to react with 1,4-quinones to form benzodifurans. In particular, the addition of compounds with an active methylene group to quinones takes place with the formation of colored intermediates and is known in the literature as the Craven reaction. On the other hand, benzodifurans are widely used in the bioorganic and medical fields, as building blocks for optoelectronic devices, organic dyes for solar panels, components in the manufacture of organic LEDs, as well as polymeric materials with a rigid structure such as Kevlar. Possibility of preparation of linear heterocyclic systems arylfuro[2’,3’:4,5]benzo[ b ]-furanes based on 2-aryl-1,4-benzoquinones was investigated. The 2-aryl-1,4-benzoquinones 1 а – і (аryl = 4-MeC 6 H 4 ( a ), 2-C 10 H 7 ( b ), 3-CF 3 C 6 H 4 ( c ), 4-COMeC 6 H 4 ( d ), 4-NHCOMeC 6 H 4 ( e ), 3-NO 2 C 6 H 4 ( f ), 3,4-Me 2 C 6 H 3 ( g ), 3-Cl-4-MeC 6 H 3 ( h ), 3,4-Cl 2 C 6 H 3 ( i )) were obtained by the reaction between arenediazonium salts and 1,4-benzoquinone under Meerwein reactions conditions. The interaction of 2-aryl-1,4-benzoquinones 1a – i with some bifunctional C-nucleophiles under the conditions of the Craven reaction was studied. It was found that esters of cyanoacetic acid (ethyl-, propyl-, allylcyanoacetates) and malononitrile react selectively with arylquinones – substituted furobenzo[ b ]furanеs 2a – с , 3a – с , 4 , 5a – e were obtained in a medium yields. The structures of the synthesized compounds were confirmed by the 1 H NMR spectroscopy and element analysis data. Keywords: 2-aryl-1,4-benzoquinones, cyanoacetic esters, malononitrile, Craven reaction, arylfuro[2’,3’:4,5]benzo[ b ]furanes.

Alkylation of CH-Acids with 3-Halomethyl Derivatives of Ethyl (Diethoxyphosphorylmethyl)furoates

Alkylation at the carbon atom of the active methylene group of 3-halomethyl derivatives of phosphonocarboxylic acid esters of the furan series with acetylacetone, acetoacetic, malonic and cyanoacetic esters in an absolute ethanol–dioxane medium (1 : 10) in the presence of sodium ethylate leads to the formation of the corresponding monoalkyl derivatives. The obtained phosphonomethylated derivatives of 3-(furylmethyl)acetylacetone and ethyl 2-(furylmethyl)acetoacetate react with hydrazine hydrate to form phosphorus-containing derivatives of (furyl)(pyrazolyl)methanes and (furyl)(pyrazolonyl)methanes, respectively. The latter in chloroform exist exclusively in enol form.

Synthesis of Pyridazin‐3(2H)‐one Derivatives by the Reaction of CH‐Acids with Dichlorodiazadienes

The reactions of 4,4‐dichloro‐1,2‐diazabuta‐1,3‐dienes with dimethyl malonate, cyanoacetic esters and ethyl acetoacetate provided straightforward access to highly functionalized pyridazine derivatives. The approach was found to be very general for the highly efficient synthesis of various pyridazine derivatives which can be isolated in moderate to excellent yields. The possibility of their subsequent functionalization was demonstrated. Moreover, the absorption characteristics in the UV/Vis‐range and luminescence were studied for all synthesized compounds.

An Air- and Water-Stable Hydrogen-Bond-Donor Catalyst for the Enantioselective Generation of Quaternary Carbon Stereocenters by Additions of Substituted Cyanoacetate Esters to Acetylenic Esters.

The chiral enantiopure cobalt(III) complex Δ-[Co((S,S)-dpen)3 ]3+ 2Cl- B(C6 F5 )4 - (Δ-(S,S)-23+ 2Cl- B(C6 F5 )4 - ; dpen=1,2-diphenylethylenediamine) is an effective catalyst, together with pyridine (10 mol % each), for enantioselective additions of substituted cyanoacetate esters NCCH(R)CO2 R' to acetylenic esters R''C≡CCO2 R'''. In the resulting adducts NC(R'O2 C)C(R)CR''C=CHCO2 R''', C=C isomers in which the CO2 R''' moiety is trans to the new carbon-carbon bond dominate (avg. ratio 98:2). These are obtained in 70-98 % ee (avg. 86 %; data for optimum R' and R'''), as determined by 1 H NMR with the chiral solvating agent Λ-(S,S)-23+ 2I- B(3,5-C6 H3 (CF3 )2 )4 - . NMR experiments show that the cyanoacetate and acetylenic esters and pyridine can hydrogen bond to certain NH groups of the catalyst. Rates are zero order in the cyanoacetate and acetylenic esters as well as the catalyst, and implications are discussed.

Highly efficient endo’- selective synthesis of (dispiro 3,2′-pyrrolidinyl) bisoxindoles containing three contiguous chiral stereocenters with two contiguous quaternary spirostereocenters

An efficient, atom economical, one-pot synthesis of endo’- selective (dispiro 3,2′-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved by three-component reaction of isatins, malononitrile (cyanoacetic ester) and 1,3-dicarbonyl compounds in water in the presence of L-proline. One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst have also been achieved in good yields. This new methodology offers many advantages of catalyst-free, mild reaction conditions, shorter reaction time, environmental friendliness, regio- and stereoselective processes in higher yields. Synopsis: One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst provides endo’- selective (dispiro 3,2′-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved in good yield. The reactions preceded under mild reaction conditions without any catalyst yields high regio- and stereoselective products up to 55–99%.

Synthesis and Cytostatic Activity of (E)-Ethyl-2-Amino-5-(3,3-Dimethyl-4-Oxobutyliden)-4-Oxo-1- (2-Phenylaminobenzamido)-4,5-Dihydro-1Hpyrrol-3-Carboxylate

Interaction of (Z)-N-(5-tert-butyl)-2-oxofuran-3(2H)-yliden-2-phenylaminobenzohydrazide (I) with cyanoacetic ester in the presence of triethylamine was used to synthesize the novel derivative (E)-ethyl-2-amino-5-(3,3-dimethyl-4-oxobutyliden)-4-oxo-1-(2-phenylaminobenzamido)-4,5-dihydro-1H-py rrole-3-carboxylate (II). The acute toxicity of this compound was studied, along with its cytotoxic activity against gastrointestinal stromal tumor (GIST) cell line T-1. Compound II showed a concentration- and time-dependent effect comparable with the antitumor compounds imatinib, paclitaxel, etoposide, and hydroxyurea.

Синтез и цитостатическая активность (<I>E</I>)-этил-2-амино-5-(3,3-диметил-4-оксобутилиден)-4-оксо-1-(2-фениламинобензамидо)-4,5-дигидро-1<I>H</I>-пиррол-3-карбоксилата

Взаимодействием (Z)-N-(5-трет-Бутил)-2-оксофуран-3(2Н)-илиден-2-фениламинобензогидразида (I) с цианоуксусным эфиром в присутствии триэтиламина синтезировано новое производное (E)-этил-2-амино-5-(3,3-диметил-4-оксобутилиден)-4-оксо-1-(2-фениламинобензамидо)-4,5-дигидро-1H-пиррол-3-карбоксилата (II). Изучена его острая токсичность, а также цитотоксическая активность в отношении клеточной линии Т-1 гастроинтестинальной стромальной опухолевой (ГИСО). Соединение II продемонстрировало концентрационнозависимый и времязависимый эффект, сравнимый с противоопухолевыми средствами — иматинибом, паклитакселом, доксрубицином, этопозидом, гидроксимочевиной.

Synthesis of Substituted 1,2-Dihydropyridines by the Reaction of (Ethoxymethylidene)cyanoacetic Ester and Arylamides of Acetoacetic Acid

The reaction of (ethoxymethylidene)cyanoacetic ester with arylamides of acetoacetic acid proceeds under heating in the presence of triethylamine or at room temperature in the presence of sodium ethoxide. According to the NMR and IR data, the intermediate adduct undergoes no other transformations but azacyclization which predominantly involves the cyano group and forms ethyl 5-acetyl-1-aryl-6-hydroxy-2-imino-1,2-dihydropyridine-3-carboxylates in yields of 30–78%. In some cases, 5-acetyl-1-aryl-2-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitriles resulting from cyclization involving the ethoxycarbonyl group were isolated as minor products (3–12%).

HPA decorated Halloysite Nanoclay: An efficient catalyst for the green synthesis of Spirooxindole derivatives

A novel heterogeneous catalyst, HPA@HNTs‐IMI‐SO3H, was designed and synthesized based on functionalization of halloysite nanotubes with ionic liquid and subsequent incorporation of heteropolyacid. The structure of the catalyst was studied and confirmed by using SEM/EDX, FTIR, XRD, ICP‐AES, TGA, DTGA and BET. Moreover, the catalytic activity of HPA@HNTs‐IMI‐SO3H was investigated for promoting ultrasonic‐assisted three‐component reaction of isatines, malononitrile or cyanoacetic esters and 1,3‐dicarbonyl compounds to afford corresponding spirooxindole in high yields and short reaction time. The reusability of the catalyst was also studied. Notably, the catalyst could be recovered and reused for three reaction runs. However, reusing for fourth reaction runs led to the decrease of the catalytic activity. Considering leaching test results, that observation was attributed to the leaching of heteropolyacids, which can be induced by ultrasonic irradiation.

Temperature‐Dependent Dynamics of Push–Pull Rotor Systems Based on Acridinylidene Cyanoacetic Esters

A series of asymmetrically substituted acridinylidene cyanoacetic esters was synthesized and analyzed for dynamic behavior and spectroscopic features. Although formally connected by a C=C double bond, the cyanoacetic ester groups behave as molecular rotors due to the electronic push–pull situation in the system. The donor–acceptor character lowers the rotational barrier and allows controlling the rotational rate by adjusting the electronic contribution of the ester substituent and changing the solvent polarity. Besides rotation, a much faster flipping motion can be assigned to the tricyclic acridinylidene motif, both of which lead to a rapid interconversion between axially chiral conformers of the system. Treatment with acid induces an intense fluorescence of the system, due to protonation of the C=C carbon on the rotor site, concomitant with the formation of a fluorescent acridinium ion. The dynamic, fluorogenic, and electrochemical behavior of three systems is compared with the aid of NMR, UV/Vis and fluorescence measurements, X‐ray structural analysis, cyclic voltammetry, and molecular modelling.

PH-induced azo-keto and azo-enol tautomerism for 6-(3-methoxypropylamino)pyridin-2-one based thiophene azo dyes

The synthetic strategy of combining functional group transformation (FGT) and post-modification (PM) is proposed to prepare two new types of 2-amino-3-cyano-4-chloro-5-formylthiophene based heterocyclic azo dyes with mono and double 3-methoxypropan-1-amine substituted pyridine components, where the terminal aldehyde radical of the 2-formylthiophene moiety is extended into imine, acetal or α,β-unsaturated cyanoacetic ester group. The evaluation of pH stability of the mono FGT products indicates that the basic stability is depended upon the π-conjugated system of the diazo components by comparing our synthesized thiophene and azobenzene based dyes, in which better electron delocalization may facilitate the proton transfer within molecule resulting in poor stability towards base. Furthermore, the intra-ring azo-keto ⇌ azo-enol tautomerism in the coupling components is suggested to explain the appearance of five isoabsorptive points in their pH-titration experiments. In contrast, all the N2,N6-bis(3-methoxypropyl)pyridine-2,6-diamine based azo dyes exhibit extremely high pH stability no matter what diazo components are used, because no proton accepting sites are present after the double FGT. It is also found that the synthesized thiophene heterocyclic dyes exhibit a large color gamut after PM. For example, the maximum absorption wavelength (λmax) is significantly red-shifted from 496 nm in the acetal compound to 590 nm in the cyanoacetic ester terminated dye.

Post-modification of 2-formylthiophene based heterocyclic azo dyes

In order to further adjust the π-conjugated system, solubility and electronic spectrum of 2-amino-3-cyano-4-chloro-5-formylthiophene based blue colored heterocyclic blue azo dyes, a post-modification strategy has been used to extend their terminal aldehyde radical into either an imine, acetal or α,β-unsaturated cyanoacetic ester group. The resultant azo-azomethine dyes exhibit slight bathochromic shifts in their UV–Vis spectra with the increase of the π-conjugated system. In contrast, acetal terminated products display good solubility in organic solvents but hypsochromic shifts in their UV–Vis spectra. It is worth mentioning that the α,β-unsaturated cyanoacetic ester derivatives show significant bathochromic shifts and improvement of solubility simultaneously originating from the presence of increased π-conjugated system as well as the terminal cyano and ester groups. It is believed that the current study could provide a practical post-modification strategy for decorating and improving the dyeing performance of certain dyes with functional end groups.

Synthesis and Cytotoxic Activity of Ethyl 2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)- 4,5-Dihydro-1H-Pyrrole-3-Carboxylates

Recyclization of 5-aryl-2,3-dihydro-2-furandione 3-benzoylhydrazones (I) induced by cyanoacetic ester produced ethyl 2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylates (IIa-g). The biological activity of the synthesized compounds, which possessed low toxicities, was investigated. Ethyl 2-amino-1-benzamido-5-[2-(4-chlorophenyl)-2-oxoethylidene]-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate (IIf) and the 5-[2-(3,4-dimethoxyphenyl)-2-oxoethylidene] analog (IIc) exhibited the greatest cytotoxicities against several connective-tissue tumor cell lines, namely, gastrointestinal stromal tumors (GISTs), osteosarcoma U2OS, and leiomyosarcoma SK-LMS-1. Ethyl 2-amino-1-benzamido-4-oxo-5-[2-oxo-2-(p-tolyl)ethylidene]-4,5-dihydro-1H-pyrrole-3-carboxylate (IIa) suppressed significantly tumor growth of GIST, LMS, and OS cell lines. Its activity against GIST cells at 10 μM was comparable with that of imatinib (1 μM) and, at lower concentrations (2.5 and 5 μM), with those of doxorubicin (0.25 μg/mL) and etoposide (40 μM), and exceeded significantly those of taxol (1 μM) and hydroxyurea (1 mM). The cytotoxicities of most of the studied compounds at 10 μM against SK-LMS-1 and U2OS cells in vitro were significantly greater than all reference drugs (doxorubicin, taxol, etoposide, etc.).

ChemInform Abstract: Organocatalytic Peroxidation of Malonates, β‐Ketoesters, and Cyanoacetic Esters Using n‐Bu4NI/t‐BuOOH‐Mediated Intermolecular Oxidative C(sp3)—O Coupling.

AbstractThe scalable title transformation of malonates succeeds in high yields whereas the reaction of β‐ketoesters and cyanoacetic esters delivers only low to moderate product yields.

Organocatalytic peroxidation of malonates, β-ketoesters, and cyanoacetic esters using n-Bu4NI/t-BuOOH-mediated intermolecular oxidative C(sp3)–O coupling

A new organocatalytic approach for the synthesis of peroxides based on СН activation of a sp3-hybridized carbon atom is reported. Peroxides were prepared in 31–89% yield by the reaction of malonates, β-ketoesters, and cyanoacetic esters with a Bu4NI/tert-butyl hydroperoxide system. The formation of the expected hydroxylation products was not observed. In the discovered reaction, tert-butyl hydroperoxide plays a dual role by acting as the oxidant and the O-reagent for the C–O coupling. The synthesis can be scaled up to generate gram quantities of the target products.

Retro-Claisen benzylation: direct use of benzyl alcohols in Pd-catalyzed couplings with nitriles.

A new strategy has been developed for the benzylation of nitriles directly from benzyl alcohols. In this process benzyl alcohols undergo retro-Claisen activation with cyanoacetic esters to generate an active electrophile and a carbanionic nucleophile. In the presence of Pd(0) these intermediates undergo catalytic coupling to generate a new C-C bond, resulting in the formation of phenyl propionitriles.

ChemInform Abstract: Simple Synthesis of Quinoxalin‐2(1H)‐one N‐Oxides from N‐Aryl‐2‐nitrosoanilines and Alkylated Cyanoacetic Esters.

N-Aryl-2-nitrosoanilines, available from the reaction of N-arylamines with nitroarenes, condense under alkaline conditions with alkylated derivatives of cyanoacetic esters furnishing quinoxalin-2(1H)-one N-oxides in good to excellent yields. The reaction involves the condensation of the carbanion with the nitroso group leading to the nitrone intermediate, followed by intramolecular acylation of the amine function.

Greener synthesis of spirooxindole in deep eutectic solvent

A simple and efficient synthesis of spirooxindole derivatives by one-pot, three-component reaction of isatins, malononitrile and different nucleophiles under catalyst-free condition in deep eutectic solvent is reported. A series of biological importance, spirooxindole derivatives were synthesized via a multicomponent reaction of isatin, or acenaphthoquinone, and malononitrile or cyanoacetic ester with 1,3-dicarbonyl compounds, naphtol and 4-hydroxycumarin in biodegradable choline chloride based deep eutectic solvent in good yields (50–95%). This green procedure has the advantages of higher yields, shorter reaction times, environmental friendliness, and easy work-up.

Synthesis and Antibacterial Activity of Oxalates and Acetamides of {2-[2-Sopropyltetrahydropyran-4-yl-4-(4-Fluorophenyl)]Ethyl}Arylamines

The reaction of cyano(2-isopropyltetrahydropyran-4-ylidene)acetic acid ethyl ester and 4-fluorophenylmagnesium bromide produced the cyanoester that was decarboxylated to the corresponding nitrile. Reduction of the latter by LiAlH4 formed 2-[4-(4-fluorophenyl)-2-isopropyltetrahydropyran-4-yl]ethylamine, reaction of which with aromatic aldehydes synthesized azomethines that were then reduced by NaBH4 to secondary amines. The last were transformed to oxalates and acetamides. It was shown that the secondary amine oxalates possessed high antibacterial activity.

ChemInform Abstract: Enantioselective Michael Addition Reactions in Water Using a DNA‐Based Catalyst.

AbstractA catalyst comprising of double‐strained DNA and a Cu(II)‐complex promote enantioselective Michael reactions of malononitrile and cyanoacetic esters to α,β‐unsaturated 2‐acylimidazoles.