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Water-soluble 1-(3,5-di-tert-butyl-4-hydroxybenzyl)isatin 3-acylhydrazones containing an acyclic, bicyclic, or pyridinium quaternary ammonium center in the acyl moiety showed antibacterial activity against some gram-positive bacteria. Derivatives with a 2,3-dimethylpyridine or diazabicyclooctane fragment exhibited the highest activity against S. aureus and B. cereus as expressed by the minimum bactericidal concentration and were 4 times more active than chloramphenicol.

Isatin derivatives are widely used in organic synthesis, in medicinal chemistry and in the chemistry of materials. This report summarizes modern trends in the synthesis of substituted indolin-2,3-diones covering the literature from 2007 to 2017. Studies on the influence of the structure of substituents in the initial substrates on the formation of the heterocyclic isatin system and the yields of the target compounds are also discussed.1 Introduction2 Oxidation of Indole Derivatives3 Cyclization of o-Aminoacetophenones4 Cyclization of N-Acylanilines5 Miscellaneous6 Conclusion

Mild opening of the five-membered ring in 1-acetylisatins by the action of an equimolar amount of 4,4-diethoxybutan-1-amine afforded 2-(2-acetamidophenyl)-N-(4,4-diethoxybutyl)-2-oxoacetamides in almost quantitative yield.

By acid-catalyzed reaction of substituted isatins with Girard’s reagent T, new water-soluble isatin-3-acylhydrazones were obtained with high yields. Their antimicrobial activity was evaluated. Selective activity against Gram-positive bacteria (S. aureus 209p and B. cereus 8035) and yeast-like fungus Candida albicans 855–653 along with low hematoxicity was established.

This microreview compiles the methods of opening of 1-acylisatin ring in reactions with primary and secondary amines published over the past 8 years.

The first examples of phosphorus-containing analogues of natural alkaloids, convolutamydines, have been obtained by aldol condensation of 4-[dialkyl(diphenyl)phosphoryl]-4-methylpentan-2-one with isatin. An unusually facile reversible process of dehydration–hydration of these phosphorus-containing hydroxy indoles has been discovered.

Reactions of 1-chloroacetyloxindole and 1-chloroacetylisatin with some secondary amines, Girard’s reagent T and thiourea were studied. All investigated reactions proceeded via cleavage of the acyl group to form 3-substituted isatin or oxindole derivatives.

A Mannich reaction of isatin with monosubstituted piperazines in the presence of aqueous formaldehyde was used to synthesize new, as well as two previously described derivatives of 1-piperazinomethylisatins, which were further converted to isoindigo derivatives. The antimicrobial activity of the obtained heterocycles was evaluated.

Oxidation of alkyl- and alkenylisatins with m-chloroperbenzoic acid proceeds with high chemoselectivity leading to the formation of 1-substituted isatoic anhydrides (benzo[d][1,3]oxazine-2,4-diones) without epoxidation of the double bond of the alkenyl substituent. This result is in accordance with the data of DFT quantum chemical calculations using the B3LYP functional in conjunction with the basis set of atomic orbitals 6-31G(d,p). The structure of the synthesized heterocyclic compounds was proved by NMR and X-ray diffraction data.

Synthetic approaches towards isoindigo derivatives and their application in medicinal chemistry as well as in the chemistry of materials are reviewed. The literature data up to 2014 are covered.

A Pfitzinger reaction of isatin with 2-methyl-(4-oxopent-2-yl)dialkyl(diphenyl)phosphine oxides was used to synthesize new derivatives of 4-quinolinecarboxylic acids, containing a phosphine oxide fragment, and screening for antimicrobial activity was performed.

In this review we generalize and analyze information about reactions between isatin and three-, four-, and five-coordinate phosphorus compounds, published between 1966 and 2014.

A series of isatin derivatives were synthesized and studied by XRD. For the first time the peculiarities of the molecule structure and crystal packing effects were analyzed. Indoline heterocycles are planar in all the investigated structures. The molecules bearing the sterically hindered substituents at nitrogen atom of indoline heterocycle have the maximum deviations of two oxygen atoms from the indoline plane. The substituent nature at nitrogen atom does not effect on the bond lengths of indoline moiety. The value of endocyclic bond angle at nitrogen not so strongly depends on the substituent and is almost equal to the one in unsubstituted isatin. In contrast to the unsubstituted isatin, where the system of classical hydrogen N H⋯O-bonds is realized, in crystals of investigated compounds there is no opportunity to reveal ones, and the crystal structure is stabilized by C H⋯O- and π–π-interactions.

The features of the synthesis of long-chain isatin and isoindigo derivatives were demonstrated by the example of bromododecyl representatives. It was shown that the synthesis of bromododecylisatin was accompanied by the formation of the bis-isatin even at low temperatures. The deoxygenation of 1-(12-bromododecyl)isatin by tris(diethylamino)phosphine led to the formation of novel bis(bromoalkyl)isoindigo which easily reacted with nucleophilic reagents resulting in amino- or chloro-derivatives and phosphonium salts. The reaction of 1,1′-bis(bromododecyl)isoindigo with isatin sodium salt in slightly alkaline medium afforded mainly IZIN-12 and bis(2,3-dioxindolin-1-yl)isoindigo. In addition, several unexpected products were separated from this reaction. .

The reaction of diverse symmetrically-substituted isoindigo derivatives with 80% aqueous hydrazine hydrate is described. The influence of the structure of the substituent on either oxindole or isatin-3-hydrazone formation is discussed.

Depending on the substituent on the phosphorus(III) atom, reactions of tris(dialkylamino)phosphines, 2-diethylamino-1,3,2-benzodioxaphosphole, and benzene-1,4-diylbis(N,N,N′,N′-tetraethylphosphonous diamide) with 1-alkylisatins lead to the formation of isoindigo derivatives, spirophosphoranes, or spirooxiranes whose structure was determined by NMR spectroscopy and X-ray analysis.

An easy, high-yield and atom-economic procedure of a C60 fullerene modification using a reaction of fullerene C60 with N-alkylisatins in the presence of tris(diethylamino)phosphine to form novel long-chain alkylindolinone-substituted methanofullerenes (AIMs) is described. Optical absorption, electrochemical properties and solubility of AIMs were studied. Poly(3-hexylthiophene-2,5-diyl) (P3HT)/AIMs solar cells were fabricated and the effect of the AIM alkyl chain length and the P3HT:AIM ratio on the solar cell performance was studied. The power conversion efficiencies of about 2% were measured in the P3HT/AIM devices with 1:0.4 P3HT:AIM weight ratio for the AIMs with hexadecyl and dodecyl substituents. From the optical and AFM data, we suggested that the AIMs, in contrast to [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), do not disturb the P3HT crystalline domains. Moreover, the more soluble AIMs do not show a better miscibility with the P3HT crystalline phase.

A series of 1-fluorobenzylated isatins and water-soluble pyridinium isatin-3-acylhydrazones on their base were obtained. The biological evaluation of novel hydrazones showed a significant dependence of their antimicrobial activity on the position of fluorine atom in benzyl substituent. The best activity showed compounds containing a 2-fluoro-6-chlorobenzyl fragment with selective action against S. aureus. The absence of hemotoxicity of both fluorine-containing products and their some non-fluorinated analogues was shown.

The Mannich reaction of isatin with different primary and secondary amines and effect of the substituent in aromatic amines on the reaction pathway is studied. The efficient high-yield synthesis of novel isoindigo derivatives by the mild deoxygenation reaction of the corresponding isatins with tris(diethylamino)phosphine is described.

Regioselective bromination of 4-phenyl-2,7-dichloro-2H-chryseno[6,5-e][1,2]phosphinine 2-oxide proceeded in the position 3 with the formation of 3-bromo-4-phenyl-2,7-dichloro-2H-chryseno[6,5-e][1,2] phosphinine 2-oxide; the structure of its 2-tert-butylamino derivative was established by XRD analysis and correlation spectroscopy.

Addition of substituted isatins to 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone, generated in situ from 3,5-di-tert-butyl-4-hydroxybenzyl acetate, to form 1-substituted hydroxybenzylisatins, is reported. On the basis of these isatins novel isatin-3-thiosemicarbazones as well as isoindigo derivatives bearing a 2,6-di-tert-butylphenol moiety were obtained. The structures of all novel compounds are confirmed by IR, H NMR and C NMR.

An easy and convenient step-by-step synthetic procedure towards the design of a novel spiroindolomethanofullerene bearing an isoindigo fragment is reported.

Synthetic approaches towards isoindigo derivatives and their application in medicinal chemistry as well as in the chemistry of materials are reviewed. The literature data up to 2014 are covered.

The reaction of 3,4,6-triisopropyl-1,2-benzoquinone with phenylacetylene and phosphorus trichloride gave 2,6-dichloro-5,7,8-triisopropyl-4-phenyl-1,2λ5-benzoxaphosphinine 2-oxide whose structure was determined by X-ray analysis.

The reaction of substituted benzyl-, aroylmethyl-, or 1-phenetylisatins with hexaethyltriaminophosphine has been shown to lead to the formation of a library of 3,3′-biindolinylidene-2,2′-diones with functionalized benzyl-, aroylmethyl-, and 1-phenetyl fragments at the nitrogen atom.

New 1-(ω-chloroalkyl)isatins were synthesized by alkylation of isatin with α-bromo-ω-chloroalkanes. The reaction of 1-(3-chloropropyl)isatin with tris(diethylamino)phosphine followed the deoxygenation path with selective formation of isoindigo derivative.

A series of novel 2′-oxospiro[cyclopropafullerene-3,3′-indolines] was synthesized. Compounds of this type have a significant potential for use as electron-withdrawing components of light-absorbing layers of solar cells.

Isatin is a widely known natural compound occurring in various plant species, e.g., Isatis tinctoria L. and Couropita guianancis aubl. [1, 2]. Isatin was also isolated as a human adrenaline metabolite [3]. Extensive studies on the synthesis and reactivity of isatins have led to the discovery of new diverse aspects of organic reactions. Numerous methods for the preparation of various heterocyclic systems have been developed starting from isatin; in particular, spiro pyrrolidines, quinolines, indoles, β-lactams, oxindoles, and other heterocycles possessing a considerable potential of biological activity have been obtained [4, 5]. Isatin derivatives containing a reactive bromoalkyl fragment have recently attracted strong interest. These compounds were used to synthesize various conjugates with known biologically active compounds (including medicinal agents) which also showed high antibacterial [6–8], antiviral [9], and antitumor activity [10, 11]. The existing methods for the preparation of N-bromoalkylisatins are few in number and are not free from disadvantages related to side formation of alkylenediisatins. In the present communication we describe a new synthetic approach to 1-(ω-bromoacyl)isatins, which is based on acylation of isatin sodium salt (I) with ω-bromoalkanoyl chlorides II and III. The reactions were carried out in anhydrous benzene at 15°C, and the corresponding 1-(ω-bromoacyl)isatins IV and V were obtained in high yields (88–89%). Compound IV was converted into isoindigo derivative VI according to the procedure described by us previously [12]. Almost quantitative formation of hexaethylphosphoric triamide (according to the P NMR data) and high yield of VI indicated that the reaction is not accompanied by side quaternization of initial phosphorous triamide.

New phosphorus-containing derivatives of quinoline-4-carboxylic acid were synthesized by the Pfitzinger reaction from isatin and dialkyl(aryl)(2-methyl-4-oxopent-2-yl)phosphine oxides.

The reaction of aminomethylisatins (isatin N-Mannich bases) with hexaethylphosphorous triamide leads to the formation of 1,1′-bis(dialkylaminomethyl)-3,3′-bis(indolin-3-ylidene)-2,2′-diones and 1,1′-bis(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H,1′H-[3,3′]bisindolylidene-2,2′-dione.

A high-yield synthesis of some novel isatin-3-acylhydrazones on the base of 5-ethylisatin derivatives and Girard's reagent T is described. Antimicrobial activity preliminary SAR study of both 1-benzylated isatins and water-soluble hydrazones was established. The most active against Staphylococcus aureus and Bacillus cereus are ammonium salts bearing 3,4-dichloro- or 4-CF3 substituents in benzyl fragment.

A reaction of 3,6-di(tert-butyl)-1,2-benzoquinone with alkynes in the presence of phosphorus trichloride leads to a predominant formation of 4-alkyl- and 4-haloalkyl-5,8-di(tert-butyl)-2,6-dichloro-2 H- benzo[e][1,2]oxaphosphinine 2-oxide. An ipso-substitution of the tert-butyl group at ortho-position to the oxygen atom of the benzophosphinine system with the formation of 4-alkyl-5- tert-butyl-2,8-dichloro-2 H-benzo[e][1,2]oxaphosphinine 2-oxide was the minor route of the reaction with alkylacetylenes. Molecular structures of 4-butyl-5,8-di( tert-butyl)-2,6-dichloro-2 H- benzo[e][1,2]oxaphosphinine 2-oxide and 5,8-di( tert-butyl)-2,6-dichloro-4-hexyl-2 H-benzo[e][1,2]oxaphosphinine 2-oxide were studied by X-ray analysis.

The reactions of 1,2-naphthoquinones with hexaethyltriaminophosphine or tri(n-butyl)-phosphine followed by bromine or hydrogen bromide treatment has been shown to lead to the quantitative formation of the new 1,2-naphthoquinones and 1,2-dihydroxynaphthalenes containing phosphorus-carbon bond. Its structure established by NMR and single crystal X-ray diffraction.

Stable reaction products of mucochloric acid with aromatic and heterocyclic thiols were synthesized and characterized. Under basic conditions the reactions proceeded with the substitution of the chlorine atom(s) by arylthiogroup(s), while in an acidic medium the hydroxy group at C 5 was substituted. Different types of new sulfur-containing products of di- and trisubstitution on the basis of mucochloric acid were obtained. In one case a new acyclic product—di-p-tolyl-2,3-bis-(p-tolylthio)butanedithioate—was isolated. The structure of all synthesized compounds was confirmed by IR, 1 H, and 13 C NMR spectroscopy; three compounds were characterized by single crystal X-ray diffraction.

Maleic anhydride undergoes C-phosphorylation under the action of tris(diethylamino)phosphine to afford 3-dihydrofuranylidene-4-phosphorylidene-oxolane-2,5,5′-trione whereas 2,3-diphenylmaleic anhydride under the same conditions turns into N,N,N′,N′-tetraethyl-2,3-diphenylbut-2-enediamide. The latter reaction can serve as a novel approach for the synthesis of dicarboxylic acids diamides from corresponding cyclic anhydrides. Their structures were established by NMR and X-ray diffraction.

ortho-Quinones are widely spread in the nature and they attract rapt attention of researchers due to the versatile biological action (antitumor agents [1] and key intermediates in the processes of development of carcinomas [2], tuberculocidal drugs [3], pharmaceuticals for treating Shagas disease [4]). On the other hand, the ready formation of semiquinolate radicals makes these compounds promising for designing polymeric photosensitive materials [5]. ortho-Quinones as a rule are prepared by oxidation of the corresponding catechols with various oxidants like silver oxide [6], sodium periodate [7], lead dioxide [8], hydrogen peroxide [9]. In many cases for the synthesis of quinines containing other functional substituents milder oxidants should be applied. In this study we for the fi rst time have developed an effi cient procedure of the oxidation of bis-catechols linked through phosphonium groups by a polyalkylene chain into the corresponding ortho-quinones by treating with bromine. The oxidation of bis-phosphonium derivatives I, II proceeds under mild conditions at room temperature affording phosphorus-containing diquinones III, IV in nearly quantitative yelds. The completion of reaction was monitored by the IR spectroscopy following the disappearance of broad absorption bands of hydroxy groups in the region 3100–3300 cm–1 and the appearance of strong narrow absorption bands in the region 1682–1692 cm–1 corresponding to the ortho-quinone fragment. The formation of the ortho-quinone fragment is

1,4-Bis(diphenylphosphino)butane and 1,5-bis(diphenylphosphino)pentane add two molecules of 6-bromo-1,2-naphthoquinone to afford bis-ylides which on treatment with protic acids are converted into the corresponding P,P’-bis(7-bromo-3,4-dihydroxy-1-naphthyl)-substituted bis-phosphonium salts.

A convenient one-step synthesis of symmetrical 1,1’-dialkyl derivatives of isoindigo is described. Key words carbenes, deoxygenation, heterocycles, regioselectivity, phosphorus. In the last years, isoindigo [1H,1’H-bis(indolin-3-yliden)-2,2’-dione] and especially it’s N- and N,N’-derivatives attract great attention not only as dyes, but as substances which possess a specific biological activity (anti-leukemia, antiproliferative, anti-inflammatory etc.). 1-4 Thus, 1-(β-D-glucopyranosyl)-isoindigo was found to be an anti-leukemia drug. 2-4 It has to be noted that the synthesis of 1-substituted isoindigo often is a multistep procedure. The best approach to the synthesis of isoindigo derivatives seems to be the dimerization of ketocarbenes generated from isatin derivatives. It has been assumed 5,6 that mixture of 3-(triphenylphosphoranyliden)-2,3-dihydro-1H-indol-2-one and isoindigo is formed with moderate yield by the reaction of triphenylphosphine with isatin and 1-methylisatin through intermediate carbene formation. However, generation of carbenes from heterocyclic -diketones under the action of trivalent phosphorus deriv-atives has been insufficiently studied.

A series of phosphorus-containing 1,2-dihydroxynaphthalenes have been obtained via the reaction of 1,2-naphthoquinone derivatives with tri(n-butyl)- or triphenylphosphine followed by treatment of the intermediate phosphobetaines with various acids. The antimicrobial activity of the synthesized compounds has been studied and the structure—activity relationship established, which gives grounds for the search for new biologically active compounds in this direction.

Isoindigo [1H,1'H-bis(indolyl-3-indeno)-2,2'-dione] and its 1and 1,1'-substituted derivatives in the recent years attract attention of researchers not only as dyes, but also as the substances with specific biological activity (antileukemic, enterohemorragic, proliferative, antiinflammation and others), inhibiting orthomonooxygenases or kinases and possessing other related properties [1–4]. 1-(β-D-glucopyranosyl) isoindigo and isoindigo glycoside have been proposed as antileilkemia means [2, 3].