Microwave-Assisted,Multicomponent, Ecofriendly Synthesis of 3-Bihetaryl-2-oxindole Derivatives Grafted with Phenothiazine Moiety

A series of 3-(3′-pyrrolyl)-2-oxindoles incorporating the phenothiazine moiety has been synthesized under both conventional and microwave heating conditions via multicomponent reaction of 3-(2-(phenothiazin-2-yl)-2-oxoethylidene)-2-oxindole derivatives, acyclic and cyclic 1,3-dicarbonyl compounds, and ammonium acetate. The resulting 2-oxindole derivatives underwent selective chloroacetylation at both the oxindole and the phenothiazine NH groups. Treatment of the dichloroacetylated compound with 2 mol of sodium azide in acetone under reflux gave the corresponding monoazide with concomitant dechloroacetylation of the N-chloroacetyl group of the oxindole ring. Huisgen 1,3-dipolar cycloaddition of the resulted alkyl azide with diethyl acetylene–dicarboxylate afforded the corresponding triazole derivative in good yield. Furthermore, the dichloroacetylated compound could be easily cyclized into 4-(3-oxo-2,3-dihydroxazolo[3,2-a]indol-9-yl)-1H-pyrrole-3-carboxylate derivative by treatment with sodium hydride in dry toluene. The yields and rate of reactions significantly improved under microwave heating conditions.     

An efficient one-pot synthesis of spiro dihydrofuran fluorene and spiro 2-hydroxytetrahydrofuran fluorene derivatives via [3+2] oxidative cycloaddition mediated by CAN

Spiro dihydrofuran fluorene derivatives were prepared via [3+2] oxidative cycloaddition of 1,3-dicarbonyl compounds to 9-benzylidene-9H-fluorene and 2-(9H-fluorene-9-ylidene)-1-phenylethanone derivatives mediated by ceric ammonium nitrate. In the case of the reaction of 9-benzylidene-9H-fluorene with acyclic 1,3-dicarbonyl compounds, spiro 2-hydroxytetrahydrofuran fluorene derivatives were obtained.     

Syntheses of 2-(trifluoromethyl)-1,3-dicarbonyl compounds through direct trifluoromethylation with CF3I and their application to fluorinated pyrazoles syntheses

Direct trifluoromethylation of 1,3-dicarbonyl compounds with CF₃I in the presence of a Fenton reagent in dimethylsulfoxide was investigated. 1,3-Diketones, 3-oxocarboxylates and 3-oxocarboxamides were readily trifluoromethylated at the methylene carbon between two oxo groups. Cycloaddition of hydrazine derivatives to the obtained 2-(trifluoromethyl)-1,3-dicarbonyl compounds provided fluorinated pyrazoles. 4-(Trifluoromethyl)pyrazole derivatives were formed from 2-(trifluoromethyl)-1,3-diketones, while 3-oxo-2-(trifluoromethyl)carboxylates or carboxamides gave 5-fluoropyrazole-4-carboxylates or carboxamides, respectively, via 3-hydrazono-2-(trifluoromethyl)carboxylates or carboxamides as an intermediate.     

Novel four-component route to the synthesis of spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives

An effective route to spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives is described. This involves reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, and benzylamine derivatives or aliphatic amines in the presence of alkyl acetoacetate (1,3-dicarbonyl compounds) in dry methanol under reflux conditions. The reactive 1:1 enaminone, which is obtained from the addition of the amine to 1,3-dicarbonyl compound, adds to the α,β-unsaturated ketone, which is formed from the reaction of isatin and 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, to produce the alkyl 1′-benzyl-2′-methyl-2-oxo-6′-phenyl-1′H-spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives in excellent yields.     

Synthesis of 1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives by the reaction of 2-chloro-1,4-benzothiazin-3-ones with ‘push-pull’ enamines

The reaction of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazines with ‘push-pull’ enamines was investigated. The reaction with the enamines occurs at the β-carbon atom in the presence of a small excess of triethylamine. As a result, a set of 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives was prepared. On acidic hydrolysis of ethyl 2-ethyl-3-(methylimino)-2-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)butanoate, a new rearrangement affording ethyl 11-ethyl-2,3-dimethyl-4-oxo-2,3,4,5-tetrahydro-1H-2,5-methano-6,1,3-benzothiadiazocine-11-carboxylate was discovered. A plausible mechanism and factors influencing the course of the reaction are discussed.     

One-pot synthesis of 2-(dicyanomethylene)-1,2-dihydropyridine derivatives

The synthesis of 2-(dicyanomethylene)-1,2-dihydropyridine derivatives from the reactions of arylmethylidene derivatives of malononitrile dimers with 1,3-dicarbonyl compounds is described.     

N-heterocyclic carbene catalyzed reaction of enals and 1,2-dicarbonyl compounds: stereoselective synthesis of spiro gamma-butyrolactones

[reaction: see text]. Nucleophilic heterocyclic carbene (NHC) catalyzed annulation of enals and cyclic 1,2-dicarbonyl compounds, opening a route to gamma-spirolactones, has been observed for the first time. The strategy works well with isatins, leading to spiroannulated oxindole derivatives. It is conceivable that the spiroannulation protocol reported herein will be applicable to the synthesis of important natural products that are endowed with a spiro gamma-butyrolactone motif, especially oxindoles and norsesquiterpenoids.     

Water-soluble 2-aminomethylidene-1,3-dicarbonyl compounds as new chalcogenide colloidal stabilizers

Reactions of 2-ethoxymethylidene derivatives of 1,3-dicarbonyl compounds with N,N-dimethylethane-1,2-diamine gave a number of 2-[(2-dimethylaminoethyl)amino]methylidene-1,3-dicarbonyl compounds which were subjected to regioselective quaternization at the tertiary nitrogen atom with methyl iodide. The resulting quaternary ammonium salts inhibited aggregation of cadmium and zinc sulfide sols in aqueous medium.     

Review of synthesis and various biological activities of spiro heterocyclic compounds comprising oxindole and pyrrolidine moities

Spirocyclic compounds isolated from plant and animal origins have important applications in medicinal chemistry. Spiro compounds having cyclic structures fused at a central carbon are of recent interest because of their interesting conformational features and their structural implications for biological systems. Spiro heterocycles like spiropyrrolidines and oxindole moieties have been found to play fundamental roles in biological processes and have exhibited diversified biological activity and pharmacological and therapeutical properties. In view of these facts we decided to present a representative synthetic scheme and various biological activities of the heterocycles like spiropyrrolidines and oxindole moieties derivatives, especially in relation to microbial infections like cancer and tubercular, viral, HIV, bacterial, and fungal infections.     

Synthesis,characterization, and investigations of antimicrobial activity of benzopyrans,benzofurans and spiro[4.5]decanes

In this study, the radical cyclization reactions of cyclic 1,3-dicarbonyl compounds (1a–c) and α,β-unsaturated alcohols (2a–d) through Mn(OAc)₃ were performed. A series of biologically interesting dihydropyrans (3–5) and dihydrofurans (6–18) were synthesized as a result of these reactions. Spiro compounds (19–20) were obtained from the reactions of 1,3-dicarbonyl compounds and (E)-2,4-diphenyl-but-3-en-2-ol (2e). The unique structure of compound 19 was also confirmed by X-ray crystallography. In addition, the antibacterial activities of synthesized compounds were screened against some bacteria. Their zone diameters showed better results than some known antibiotics.     

Reactivity of 2-methylene-1,3-dicarbonyl compounds. 1,3-dipolar cycloaddition reaction with ethyl diazoacetate.

The reaction of 2-methylene-1,3-dicarbonyl compounds (1) with ethyl diazoacetate gave 4,5-dihydro-1H-pyrazole derivatives (2), which were stable for several months at room temperature in good yields.     

Synthesis and [3+2] cycloaddition reaction of 3‐[(trimethylsilylmethylamino)(methylthio)‐methylene]heterocyclic compounds

3‐[(Trimethylsilylmethylamino)(methylthio)]methylene‐2‐coumaranone ( 4a ) and 1‐methyloxindole ( 4b ), readily prepared by reactions of the corresponding bis(methylthio)methylene heterocyclic compounds ( 2a, b ), with (trimethylsilylmethyl)amine (3), were found to be synthetic equivalents of heterocyclic alkylidene‐azomethine ylides. Reactions of 4a, b with reactive heterodipolarophiles such as aldehydes and ketones and reactive alkenes in the presence of cesium fluoride gave the 1,3‐dipolar cycloadducts, 3‐(2‐oxazoli‐dinylidene)‐oxindole and ‐coumaran‐2‐one derivatives ( 8a‐j, 9a‐h ), as well as pyrrolylidenecoumaran‐2‐one and oxindole derivatives ( 12‐15,17,18 ), via the 1,3‐elimination of (methylthio)trimethylsilane.     

Synthesis and properties of 2-azahetarylaminomethylidene 1,3-dicarbonyl compounds

Reactions of 2-ethoxymethylidene 1,3-dicarbonyl compounds with pyridine-2,6- and pyrimidine-4,5-diamines gave the corresponding 2-hetarylaminomethylidene derivatives. Depending on the initial reactant structure, the formation of mono-and/or bis-condensation products is possible. Hetarylaminomethylidene derivatives showed a moderate tuberculostatic effect. 2-Pyridinylaminomethylidene 3-oxo esters were used as ligands to obtain coordination compounds with d- and f-metal ions.     

Efficient Syntheses of New 2,2′-Disubstituted-2,3-dihydrofuran Derivatives and Natural Polyketide Analogues

Efficient syntheses of new 2,2′-disubstituted-2,3-dihydrofuran(5H)-4-one,spiro{benzofuran-2,2′-bicyclo[2.2.1]heptan}-4(5H)-one derivatives, and natural polyketide analogues have been achieved via the oxidative [3 + 2] cycloaddition of 1,3-dicarbonyl compounds with monoterpenes myrcene, camphene, and natural phenyl propenes, namely anethole and safrole respectively. Interestingly, the reaction of isoprene and myrcene with 1,3-dicarbonyl compounds yielded 2,2-disubstituted tetrahydrobenzofuran-4(5H)-one derivatives at room temperature. Thus, several substituted 2,3-dihydrofuran derivatives (3a–3h) with potential biological activity have been synthesized.     

Facile one pot microwave induced solvent-free synthesis and antifungal, antitubercular screening of spiro [1,5]-benzothiazepin-2,3'[3'H]indol-2[1'H]-ones

Microwave activation coupled with dry media technique as a green chemistry procedure has been applied to synthesis of a series of some new title compounds. They have been obtained by the reaction of in situ synthesized 1,3-dihydro-3-[2-(phenyl/4-fluorophenyl)-2-oxoethylidene)-indol-2(1H)-one (4a, b) with substituted aminobenzenethiols (5a-d). The key intermediates 4a, b were also prepared in one step by this improved technique by reacting isatin and substituted acetophenones (2a, b). The results obtained under microwave irradiation when compared with that following conventional method demonstrate the versatility of the process. The title compounds 7a-e have also been screened for their antifungal and antitubercular activity, 7a and 7e showing maximum inhibition of growth of Alternaria alternata and Fusarium oxysporium and 7b, c, e revealing significant antitubercular activity.     

Synthesis and Electrochemical Oxidation of Nitriles of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic Acids

Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-1,4,5,6-tetrahydropyridine-3-carboxylic acids were obtained by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate with iodoacetamide or by a three-component synthesis by condensing 2-arylmethylene-1,3-dicarbonyl compounds with 2-cyanothioacetamide in the presence of piperidine with subsequent reaction with iodoacetamide. Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acids were obtained by the dehydration of 6-hydroxy-1,4,5,6-tetrahydropyridines or with a one-reactor three-component system from 2-cyano-3-(4-methoxyphenyl)thioacrylamide, 1,3-dicarbonyl compounds, and iodoacetamide. The electrochemical oxidation of the synthesized nitriles was investigated and it was established that derivatives of 1,4,5,6-tetrahydropyridine as a rule are oxidized readily to the corresponding 1,4-dihydropyridines. A comparative analysis has been carried out of the ability of hydrogenated pyridines to be oxidized electrochemically depending on the electron-withdrawing properties of the substituents in the heterocycle.     

1,2,3‐Triazole derivatives of 3‐ferrocenylidene‐2‐oxindole: Synthesis,characterization, electrochemical and antimicrobial evaluation

A series of bioactive, triazole‐linked benzyl, aryl, sugar and aliphatic conjugates of 3‐ferrocenylidene‐oxindole have been synthesized. A facile 1,3‐dipolar‐Huisgen coupling reaction of the respective azides with the 3‐ferrocenylidene‐oxindole N‐propargyl moiety ( 3 ) gave the corresponding conjugates ( 5a–n ). All the newly synthesized compounds ( 5a–n ) were characterized by ¹H‐NMR, ¹³C‐NMR, HRMS, Fourier transform‐infrared spectroscopy and elemental analysis. The UV–Vis and electrochemical studies of these compounds were performed in dimethylsulfoxide solutions. The structure of compound ( 3 ) was determined by single crystal X‐ray diffraction study. These compounds exhibited moderate to good antimicrobial activity against Gram‐positive and Gram‐negative strains.     

Synthesis of 3,4-dihydropyridin-2-one derivatives in convergent mode applying bio catalyst vitamin B1 and polymer supported catalyst PEG-SO3H from two different sets of building blocks

Two highly efficient, green protocols have been developed for the synthesis of 3,4-dihydropyridin-2-one derivatives from different starting materials exploring two reaction specific catalysts, vitamin B₁ (VB₁), and PEG-SO₃H. VB₁ catalyzed simple and convenient protocol has been developed for the synthesis of 3,4-dihydropyridin-2-one derivatives by the installation of aldehyde, cyanoacetamide, and 1,3-dicarbonyl compounds. In addition, 3,4-dihydropyridin-2-one derivatives have also been synthesized by simply combining aldehyde, malononitrile, and 1,3-dicarbonyl compounds via the formation of 4H-pyran nucleus and PEG-SO₃H catalyzed one-pot rearrangement.     

Cu(OTf)2 catalyzed cross-coupling reaction of 1,3-dicarbonyl derivatives with 2-oxo-1-pyrrolidine compounds

An efficient method for the cross-coupling reactions of 1,3-dicarbonyl compounds with 2-oxo-1-pyrrolidine compounds 1 was developed. Cu(OTf)₂ catalyzed C–C bond forming reactions using substrates 1 with 1,3-dicarbonyl compounds in chloroform, providing the corresponding compounds of 2-oxo-1-pyrrolidine bearing 1,3-dicarbonyl moiety in moderate to good yields.     

Direct introduction of heterocyclic residues in the oxindole ring

It has been reported [1] that salts of some N-acyloxyheteroaromatic cations hetarylate 1-methyloxindole in situ. It seemed extremely probable that the salts of more electrophilic N-acylheteroaromatic cations also can be used for the direct introduction of a heterocyclic residue in the oxindole ring, especially since similar salts have proved to be suitable for the hetarylation of the most diverse CH acids with pK_a 20–21 [2].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1371–1373, October, 1979.