Oxindoles 3- amino-2-oxindole

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). 

Dipolar cycloadditions of the unusual dipolarophiles 9-arylidenefluorenes 446 with the dipoles generated from isatin 432a and cyclic amino acid proline 433a were carried out under four different conditions to yield a series of novel dispiro oxindole derivatives 50a-f via [3+2] cycloaddition (Scheme 100) <2002T8981>. 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

To test the generality of this reaction, the indole systems 70a,b were prepared from hexahydro-8-oxopyrrolo[ 1,2-a]indole 67 and tetrahydro-4-oxindole 68 (Scheme 11). These compounds in turn were readily obtained from cyclohexane-1,3-one and the appropriate amino acid salt according to Franck s pyrrole acylation protocol.53 Attempts to directly oxidize 67 or 68 to the hydroxyindole oxidation state using DDQ met with failure despite numerous attempts involving variation in solvent and reaction temperature. To circumvent this limitation, it was reasoned that... 

Another method of building up the physostigmine ring system was devised by the same authors who devised the first (35). In this method, the pyrrolo ring was closed by reaction of an appropriately amino-substituted oxindole (XV) with phosphorus pentoxide to yield the cyclic amidine XVI, which was subsequently reduced to XVII and then methylated to give a product claimed to be dl-esermethole (characterized as the methopicrate). 

Another pathway of peroxynitrite-mediated modification of aromatic amino acid residues is hydroxylation. Products of peroxynitrite reaction with phenylalanine include p-, m-, and o-tyrosine. Peroxynitrite also forms dityrosine from tyrosine (V2). Major products of oxidative modifications of tryptophan by peroxynitrite include hydropyrroloindole, oxindole, and IV-formylkynurenine (K4). 

All of these compounds which we have given as related to anthranilic acid and to indigo are plainly derivatives of ortho-amino aromatic acids, either benzoic acid itself, as in anthranilic acid and anthranil, or side-chain-carboxy acids, as in isatin and oxindole. 

Oxindole.—When ortho-nitro phenyl acetic acid is reduced to the ortho-amino phenyl acetic acid, the latter, being a gawwa-amino acid, loses water yielding a lactam which is known as oxindole. 

Di-oxindole.— Similarly a di-hydroxy compound known as di-oxin-dole is obtained as a lactam anhydride from ortho-amino mandellic acid, ortho-amino phenyl hydroxy acetic acid. 

Two ° independent and different degradations have been carried out to establish the absolute stereochemistry, and in each case the final compound contained only the C(3a) asymmetric centre. One approach was to degrade the alkaloid to the oxindole (10), the enantiomorph of which was then synthesised starting from (R)-( — )-2-methyl-2-phenylbutyric acid. In the second approach the molecule was broken down to an amino-acid (11) which was characterised as its 2,4-dinitrophenyl derivative. Its enantiomer was synthesised from 3-ethyl-3-methoxycarbonyl-3-methylpropionic acid of known absolute configuration. 

Amino-2-oxindole catalyzes the decarboxylation of a-keto acids. 

Indole, CgHyN, is of interest on account of its relation to indigo (667) and the fact that it is the product of the decomposition of certain proteins. Syntheses of indole lead to the conclusion that it is made up of a benzene nucleus condensed with a pyrrole nucleus. When o-nitro-phenylacetic acid is reduced with tin and hydrochloric acid the amino-phenylacetic acid formed loses water spontaneously and passes into oxindole —... 

Kiindig and coworkers have studied a variety of chiral A-heterocyclic carbene ligands, e.g., 49, for the synthesis of all-carbon or heteroatom containing (methoxy or amino) quaternary centers at oxindole C3 [33, 34]. For example, oxindole 50 was prepared via asymmetric intramolecular cyclization of the corresponding o-bromoanilide 48 in 94% ee (Scheme 14). 

Isatins have served as valuable precursors for the preparation of oxindoles bearing amino functionality at stereodefined C3. In a report from the Emiua group, isatin derived oxime 91 (Scheme 25) was transformed to the urea derivative 92 which underwent a diastereoselective alkylation at C3 to afford the /-menthol adduct 93 (94 6 dr) [59]. Lithium counterions proved to be more effective than potassium ions for achieving diastereocontrol of the enolate alkylation a mechanism has been suggested involving lithium ion chelation between the oxindole enolate of 92, the carbonyl of the urea fimctionality at C3, and the carbonyl of the menthyl ester electrophile. 

Silvani and coworkers have converted isatin to the chiral imines 94 and 97 that were employed as electrophiles for the diastereoselective addition of Grignard reagents [60]. As illustrated in Scheme 26, addition of allyl Grignard to 94 or 97 afforded the amino-substituted quaternary oxindoles 95 or 98 with good diastereos-electivity (80 20 and 89 11 dr, respectively). Grignard adducts 95 and 98 were further manipulated to afford the enantiomeric pair of 3-amino-3-allyloxindoles (5)-96 and (R)-99, respectively. 

The Barbas group has employed a cinchona alkaloid to direct an enantioselective a-amination of oxindoles using diethyl azodicarboxylate as the electrophilic species (Scheme 27) [61]. In one example, A-benzyl protected 3-methyloxindole 100 was transformed to the amino-substituted oxindole 102 in 91% ee using (DHQD)2PHAL... 

The Marsden group has published a collection of articles detailing the synthesis of heteroatom containing C3 quatemized oxindoles [64—66]. The transformations involved the palladium-catalyzed intramolecular arylation of anilides bearing either amino or alkoxy functionality alpha to the anilide carbonyl. Under microwave conditions, a variety of 3-alkoxy-3-aryl, 3-amino-3-aiyl, or 3-amino-3-alkyloxin-doles have been prepared in racemic form. In one example, 3-indolyloxindole 1 7 was prepared in 65% yield (Scheme 28). 

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