3.3- Dimethyl oxindole

Mixtures of products are frequentiy observed. Oxidation by peroxycarboxylic acids usually give similar products (22). Several chemical oxidants give good yields of specific oxidation products. Dimethyl sulfoxide in aqueous acid gives oxindoles (23). In methanol, MoO HMPA (hexamethylphosphoramide) gives 3-hydroxy-2-methoxyindolines (24). 

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). 

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. 

Winterfeldt and Nelke have shown that oxindole reacts with DMAD in presence of sodium hydride to give dimethyl oxindolylidine-3-succinate (204). However, when the reaction is carried out in the absence of any base, at around 200°, the products formed are the azepine derivative 205, the carbazole 206, and the furan 207 (Scheme 32). Similarly, the reaction of iV-methyloxindole with DMAD in presence of sodium methoxide gives rise to AT-methyloxindolylidine-3-succinate. ... 

Oxindoles are prepared using a solid-phase Pummerer reaction. Thus, the immobilized amide 182 undergoes the Pummerer rearrangement on treatment with TFAA and boron trifluoride diethyl etherate (BF3 Et20) (Equation 118). Cleavage of the oxindole from the linker is achieved using samarium iodide and 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) <2003CC2380>. 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

Dimethyl acetylenedicarboxylate and the oxindole anion gave 295 (R = H), which was hydrogenated to 296,185 but oxindole with DMAD at 200° gave the furan 297,186 clearly derived by self-condensation of the ester, and the benzazepine 298 the structure and origin of which require further investigation. 

This and other evidence (16) indicated that eseretholemethine (VI R = C2H5) was a pseudo base or carbinol amine. Thus, on oxidation with silver nitrate an oxindole was obtained (dehydroeseretholemethine, VII R = C2H5), which on subsequent Hofmann degradation and reduction of the Hofmann elimination product gave 5-ethoxy-l,3-dimethyl-3-ethyloxindole (13). The methyl homolog (VII R = CHa),... 

Cyclization of the anilide 213 using TiCU produced the 3-chloro-substituted oxindole 214 (Equation 69), whereas a similar reaction induced by BF3-OEt2 gave the corresponding methoxy-substituted derivative <1998T4889>. Lewis acids have also been used in an approach to indole-2-carboxylates based on cyclization of (Z)-A(A -dimethyl-aminopropenoates derived by exposure of A -arylglycinates to DMEDMA <2006SL749>. 

The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2-vinylindoles from A-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an A-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. 

The bisoxindole (19) is built up as followsoxidative coupling of N-methyl-oxindole gives iV( )iV(o.)-dimethyl-3,3 -bisoxindole which can be alkylated, using chloroacetonitrile, at the 3 and 3 positions. Reduction of the resulting dinitrile... 

Hydroxy-indole409-411 (Oxindole) erfahren wie 3-Hydroxy-lH-isoindole412 durch iiberschiissiges Chlormethyl-dimethyl-iminium-dichlorphosphat Chlorformylierung zu 2-Chlor-3-formyl-indolen bzw. 3-Chlor-l-formyl-lH-isoindolen ... 

Treatment of 2-hydroxytryptamine (406) with dimethyl 4-ethyl-4-formylpimelate (540) gave two isomeric oxindoles (542 and 543) differing in the stereochemistry of the ethyl group. The most polar product (542) was heated for 2 hr under nitrogen in the presence of polyphosphoric acid to afford 3-oxo- 1,2-dehydroaspidospermidine (504) in 68% yield (Scheme 32). The stereochemistry of this polar product must therefore be that... 

The total synthesis of d/-21-oxo-gelsemine reported by Hart and collaborators (107) features two free radical cyclizations (C-5-C-16 bond formation in gelsemine) to construct both a tricyclic substructure 314 in the terpene part of gelsemine and the spiro-oxindole moiety. The synthesis was initiated with the Diels-Alder reaction between A-methylmaleimide and the diene 302, followed by treatment of the crude cycloadduct with 2,2-dimethyl-l,3-propanediol and a catalytic amount of p-toluenesulfonic acid, to give the perhydro-isoindole 304 in 43% yield. By application of the Grieco dehydra-... 

This was followed shortly by a stereo- and enantiocontrolled synthesis of (—)-chimonanthine (154) and calycanthine (150) as well as a second route to meso-chimonanthine (152). The central step in this synthesis features the use of a double Heck cyclization to create vicinal quaternary carbon centers in high yields and with complete stereocontrol 124). The synthesis commenced with a double alkylation of the lithium dienolate of dimethyl succinate 194 and tartrate-derived diiodide 195 to give a diastereomeric mixture of the saturated diesters. Subsequent oxidation of the diesters, followed in succession by aminolysis, A-benzylation, removal of the benzyl ethers, and silylation, provided the cyclization substrate 197, which on Heck cyclization yielded a single product, 198, a pentacyclic bisoxindole, subsequently shown to have the meso relationship of the two oxindole groups. Further manipulations of 198 led eventually to the diazide derivative 199, which can be processed to we.so-chimonanthine (152), following the procedure established in the preceding synthesis (Scheme 14). 

Oxindole and dimethyl acetylenedicarboxylate in abs. dioxane treated slowly with a 50 -dispersion of NaH in mineral oil, and the product isolated after 2 hrs. at room temp. 3-[l,2-bis(methoxycarbonyl)ethylidene]oxindole. Y 80%. E. Winter-... 

Wierenga discovered that borane-dimethyl sulfide reduced 3-(alkylthio)oxindole 5 to the desired indole (Scheme 3, equation 1), because LAH was sluggish or completely ineffective [15]. Subsequently, Wierenga generalized this smooth reduction of 3-(alkylthio)oxindoles (equation 2) [16]. Also reduced to 3-alkylindoles with BH -SMe were 3-hydroxyoxindoles (88-93%), which were prepared from isatins by selective C-3 addition of Grignards. Sano and coworkers used aluminum hydride to reduce 3-(phenylthio)oxindole 6 to the desired indole (equation 3)... 

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