Oxindole, 3-

Oxindole exists as the carbonyl-tautomer, the hydroxy 1-tautomer ( 2-hydroxyindole ) being undetectable. There is nothing remarkable about the reactions of oxindole for the most part it is a typical 5-membered lactam, except that deprotonation at the p-carbon (pA a 18) occurs more readily than with simple amides, because the resulting anion is stabilised by an aromatic indole resonance contributor. Such anions will react with electrophiles like alkyl halides and aldehydes at the p-carbon, the last with dehydration and the production of aldol condensation products. Oxindoles can be oxidised to isatins (20.13.3) via easy 3,3-dibromination, then hydrolysis. Bromination of oxindole with A -bromosuccinimide gives 

The interaction of oxindole with the Vilsmeier reagent produces 2-chloro-3-formylindole efficiently this difunctional indole has considerable potential for elaboration, for example nucleophilic displacement of the halogen, activated by the orf/to-aldehyde, can produce indoles carrying a nitrogen substituent at C-2.  

Of potential in palladinm(0)-catalysed conpling processes to the indole 2-position is the 1-phenylsnlfo-nylated 2-triflate readily obtained from 1-phenylsnlfonyloxindole (see also 4.2.3).  

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When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

In 1991, we proposed in our 1-Hydroxyindole Hypotheses (91YGK205) that some types of 1-hydroxyindoles (117) would undergo a rearrangement reaetion to provide 2-oxindole 118 and/or 3-oxindole 119 as illustrated in Seheme 18. As suitable substrates for realizing the predietions, we have sueeeeded in finding l,2,3,4-tetrahydro-9-hydroxy-/3-earboline eompounds 11 and 16a. 

Indolones and isoindolones have been utilised in the synthesis of fused azepine derivatives. In the one reaction, rearrangement of the alkynes 18 to 2-benzazepine-l,5-diones 19 in the presence of Lewis acids has been reported <96XL393>. Xhe yields vary from moderate to very good. Xricyclic azepines 20 are obtained by the reaction of the 4-[2 -(p-toluenesulfonyloxy)ethyl]-2-oxindole with imines <96JHC209>. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

There continues to be interest in small-molecular scaffolds as good starting points for drug discovery [50]. Indoles [51], 2-oxindoles [52], 2-arylben-zothiazoles [53], rhodanines [54], quinolones [55], (3-D-glucose [56], and y-pyrones [57] have all recently been reviewed as "privileged" scaffolds. 

Spiro-2-oxindoles, such as 331, are readily crafted from the Pd-catalyzed reactions of o-haloanilines with vinyl halides and triflates in the presence of CO [428]. The o-iodo enamide is presumed to form initially, followed by Heck cyclization. 

Scheme 68 2-Oxindol derivatives by nickel-catalyzed cyclization of aryl halides.

Diazo-2-oxindole (21c) reacted with benzyne and dimethyl acetylene-dicarboxylate in dichloromethane at 41°C to give polycyclic ring systems of type 265 (73TL1417) (Scheme 78). The intermediate spiro adducts 264 could not be detected, but it is reasonable to suppose that the final products were obtained by [1,5]sigmatropic rearrangement of the carboxamido moiety. 

The unconventional 3-diazoindoles were prepared by oxidative conversion of hydrazones and oximes. Thus, l-methyl-3-diazo-2-oxindole (21d) was prepared by mercuric oxide oxidation of l-methylisatin-3-hydrazone 297 (X = NNH2) in benzene at room temperature (1891JPR551) (Scheme 91). It can also be prepared by decomposition of l-methylisatin-3-tosyl-hydrazone 297 (X = NNHTs) with aqueous sodium hydroxide in a two-... 

Vilsmeier reaction of 2-oxindole (830) afforded 2-chloroindole-3-carbaldehyde (891). Suzuki cross-coupling of 891 with furan-3-boronic acid (1124), followed by protection of the indole nitrogen with benzyloxymethyl (BOM) chloride, led to... 

Arumugam, V. Routledge, A. Abell, C. Balasubramanian, S. Synthesis of 2-Oxindole Derivatives via the Intramolecular Heck Reaction on Solid Support, Tetrahedron Lett. 1997, 38, 6473-6476. 

Many early claims of having prepared simple 1-hydroxyindoles have proved to be unfounded, although the unusually stable l-hydroxy-2-phenylindole was obtained in 1895.1-Hydroxyindole itself polymerizes on attempted isolation, while O-acylation, O-alkylation, or the presence of substituents greatly stabilizes the molecule. One 1-hydroxyindole antibiotic has been identified and is the only 1-hydroxyindole derivative isolated from natural sources so far. In contrast, a substantial number of 1-methoxyindoles occurs in various plants, and some of these may inhibit tumor formation in mammals. The biochemistry of these compounds, which include 1-methoxy-indoles, -indolines and -2-oxindoles, has not been widely investigated and could be a very fruitful area for new research which might well lead to novel medicinal agents and other useful compounds. 

The 3-methylene group of l-methoxy-2-oxindole (163) is easily ionized to give a carbanion that undergoes well-known types of reactions with alkyl halides or activated olefins without loss of the methoxyl group (e.g. 

Reduction of2-nitrophenylacetic acids. The best method of preparing l-hydroxy-2-oxindole is the reduction of methyl 2-nitrophenylacetate (169) with zinc and ammonium chloride and immediate acetylation... 

Photolysis. l-Hydroxy-2-oxindole (162) is reportedly formed from 2-(2-nitrophenyl)ethanol by UV irradiation in several solvents (70ACS2650). The main product of the irradiation of dissolved or powdered 174 is the 1-hydroxyindolone 175, which is formed by the initial attack of the excited nitro group on the r-butyl group (75CB3843). A great deal of mechanistic work has been done on... 

About a dozen l-methoxy-2-oxindole alkaloids have been isolated and identified, either by X-ray crystallography or by sophisticated spectroscopy. Most are associated with their des-l-methoxy analogues in the plants. Very little chemistry involving the l-methoxy-2-oxindole ring system of these compounds has been done, and they will therefore be considered only briefly. 

Gelsemicine (234) was the first naturally occuring l-methoxy-2-oxindole to be discovered in Gelsemium sempervirens roots (65MI3). Its structure... 

The lithium aluminum hydride reduction of l-acetyloxy-2-oxindole (287) gave a polymer, but that of the 1-methoxy analogue (288) yielded [78JCS(P1)1117] 1-methoxyindole. Application of this method (83H1797) led to a valuable synthesis of lespedamine 291. Alkylation of 288 by 1,2-dibromoethane and sodium hydride gave a 3,3-spiro derivative, which dimethylamine converted to 289. Reduction with lithium aluminum hydride now gave 290, as a mixture of isomers, which was dehydrated instantly by acid to 291 (see Section 1II,E). 

Oxidation of IAA (2.49) results in cation 2.50, which undergoes decarboxylation and results in the skatolyl radical (2.51). This compound reacts with molecular oxygen to form peroxyl radical 2.52. With IAA or another cellular reductor, the hydroperoxide 2.53 is formed. It is this compound that activates the peroxidase, and thus allows the oxidation of other substrates, such as coniferyl alcohol. Among the degradation products of 2.53, 3-methylene 2-oxindole (2.54) is the most abundant. 

Folkes, L. K., Rossiter, S., and Wardman, P., 2002, Reactivity toward thiols and cytotoxicity of 3-methylene-2-oxindoles, cytotoxins from indole-3-acetic acids, on activation by peroxidases, Chem. Res. Toxicol. 15 877-882. 

With excess of Br2, further bromination products of the central ring were obtained. 3-iV-Aryl-2-oxindoles (55) undergo Hofmann-Martius rearrangement under acid-catalysed conditions, in contrast to their 3-0 analogues (Scheme 16).53 The thermal... 

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