Reduction oxindoles

The reduction of o-nitrophenyl acetic acids or esters leads to cyclization to oxindoles. Several routes to o-nitrophenylacetic acid derivatives arc available, including nitroarylation of carbanions with o-nitroaryl halides[2l,22] or trif-late[23] and acylation of o-nitrotoluenes with diethyl oxalate followed by oxidation of the resulting 3-(u-nitrophenyl)pyruvate[24 26]. 

The Gassman synthesis has been a particularly useful method for the synthesis of oxindolcs[lb,8]. Use of methylthioacetate esters in the reactions leads to 3-(methylthio)oxindoles which can be desulfurized with Raney nickel. Desulfurization can also be done by reduction with zinc or tin[10,ll]. 

The Gassman indole synthesis has one serious limitation. Attempts to use anilines with an ortho/para- methoxy moiety failed to indolize. One means to overcome this was synthesis of the corresponding oxindoles followed by reduction to the indoles. ... 

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines. When diphenylamine reacts with chloro-propionyl chloride, amide 40 results this in turn readily cyclizes to oxindole 41. Sodium hydride followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion) partial demethylation is accomplished by refluxing with ethylchiorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity. ... 

Nitrophenylpyruvic acid was reduced to oxindole using iron pin-dust-ferrous sulfate in water. The iron oxide-iron residues, after filtering and washing with chloroform, rapidly heated in contact with air and shattered the Buchner funnel [1], Previously, rapid heating effects had been observed on sucking air through the iron oxide residues from hot filtration of aqueous liquor from reduction of a nitro compound with reduced iron powder [2],... 

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

Methyloxindole has been prepared by the reduction of a-(2-nitro-phenyl)propionic acid,2 by heating j8-propionylphenylhydrazine with lime3 or with sodium alkoxides,4 and by reduction of the benzoyl derivative of oxindole-3-aldehyde.6... 

The known pyruvic acid 87 [Fig. (25)] [54] was oxidatively decarboxylated [55] to afford the phenylacetic acid 88, which was reductively cyclized to give the required oxindole 89 in nearly quantitative yield. 

There are several reports of methods that will selectively reduce a tertiary amide in the presence of a secondary amide[59]. The secondary lactam of 101 was protected as the lactim ether 107 and treated with diborane however, the spectral characteristics of the major products isolated were consistent with reduction of both the tertiary amide and the lactim ether. In 1991 Martin et al. [60] successfully used alane to reduce a tertiary amide in the presence of an oxindole (secondary amide) relying on the known rate difference for reduction between these two groups [61]. 

A major group of photochemical reduction reactions are oxidation-reduction processes. As typical examples, phenazine (CXXI) and alloxan (CXXIII) are reduced by ethanol to give dihydrophenazine (CXXIl)/ 2 and alloxantin (CXXIV).42 Isatin (CXXV) in the presence of ace-naphthene (CXXVI) is reduced to isatide (CXXVII).204 The photoreaction proceeds at the expense of the alcohol, or (CXXVI) acetaldehyde and acenaphthylene (CXXVIII), are formed as by-products respectively. The formation of CXXVII may be due to the interaction of CXXV with the intermediate oxindole (CXXIX). 

Dihalogenation of oxindole followed by alkaline hydrolysis of the 3,3-dihalooxindole has been applied to the synthesis of some isa-tins.66,126,136 137b A number of oxindoles have been treated with nitrous acid to give isatin-3-oximes.100,138 Reduction of the oximes to 3-aminooxindoles followed by ferric chloride oxidation gave isatins.100,138 When this sequence was applied to 7-azaoxindole, the azaisatin 33 was... 

Catalytic hydrogenation of isatin and A-methylisatin gave oxindole and jV-methyloxindole,256 while similar reduction of 1-azidoacetylisatin gave 1-aminoacetyloxindole.165 Catalytic hydrogenation over platinum oxide of A-methylisatin and isatin-1-propionic acid gave 70.169 A... 

An analytical procedure for organotin hydrides has been based on the reduction of isatin to oxindole.273... 

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... 

The chlorosulfonium compounds can also be used for the synthesis of oxindoles, the stable tautomeric form of 2-hydroxyindoles. The a -methylthio ketone is replaced by ethyl methylthioacetate and the products of the Sommelet-Hauser rearrangement are cyclized to 3-methylthiooxindoles. The methylthiooxindoles are reductively desulfurized with Raney nickel (equation 102) (74JA5508). 

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). 

The first microwave-assisted Wolff-Kishner reduction was described by Parquet and Lin in 199763. The transformation of isatin to oxindole was performed on a small scale in a domestic microwave oven in two steps with a total reaction time of 40 s, as compared to 3—4 h if classical heating was utilised (Scheme 4.36). The first step involved the transformation of the carbonyl group into the hydrazone with 55% hydrazine in ethylene glycol and medium power microwave irradiation for 30 s. In the subsequent reduction step, KOH in ethylene glycol was used to substitute the more hazardous sodium ethoxide. The reaction mixture was irradiated for 10 s and the product was obtained in a yield of 32%. 

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... 

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). 

New syntheses of iVN-dimethyltryptamine and O-methylbufotenine, by way of dimethylaminoacetylation of the parent oxindole followed by reduction stages, have been reported 19 this constitutes a new and convenient route to tryptamine derivatives. 

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