Hydroxylations of oxindoles

Scheme 24 Enantioselective hydroxylation of oxindoles with molecular oxygen...

An organocatalytic asymmetric hydroxylation of oxindoles by molecular oxygen as an oxidant using a phase-transfer catalyst was reported by Itoh et ai, in 2008. The use of O2 as the oxidant was a paramount process, because it is inexpensive and environmentally benign. In these conditions, the reaction of a series of 3-substituted oxindoles in the presence of a cinchonidine-derived... 

Catalytic asymmetric hydroxylation of oxindols with molecular oxygen under biphasic conditions with PTC 24 as a catalyst could be applied to the synthesis of CPC-1 146 (Scheme 4.34). The oxidation of the 3-allyl-2-oxindole 147 under the atmosphere of air was... 

A particular type of hydroxylation of aromatic compounds is the hydroxylation of indoles (XIII), which yield biologically active oxindoles (XIV) in nearly quantitative yields (Scheme VIII) [79],... 

Indole reacts readily with electrophilic brominating agents such as Al-bromo-succinimide [36] and pyridinium bromide perbromide [37], In hydroxylic solvents oxindoles are formed by hydrolytic capture of the 3-bromoindolenine intermediate [46]. Recently, indole was among a number of reactive aromatics brominated using NBS under UV irradiation. A good yield of 3-bromoindole was reported, but the mechanism under these conditions is not clear [47]. 

Given the variety of methods for accessing 3-alkyl or 3-aryl oxindoles in racemic form, the direct asymmetric hydroxylation of 3-substituted oxindoles represents a conceptually appealing strategy for controlled installation of hydroxyl-bound... 

The spiraled architecture of welwitindolinone A isonitrile 196 has inspired the development of a variety of strategies for its construction. A beautifully simple protecting group-free synthesis of (-F)-welwitindolinone A has been achieved by Baran and coworkers [115-117]. As depicted in Scheme 48, the key step for installation of the aU-carbon quaternary center at oxindole C3 involved fluoro-hydroxylation of (—)-fischerindole 1 194 via treatment with aqueous Xep2. The desired natural product, 196, was obtained as a single diastereomer in 44% yield. The origin of the asymmetry at oxindole C3 can be traced back to enantiopure carvone oxide. 

The reaction of A-arylacrylamides and simple alcohols in the presence of 70% aqueous solution of TBHP leads to metal-free synthesis of 3,3-disubstituted oxindoles. A series of hydroxyl-containing oxindole derivatives could be prepared using this method. The reaction is proposed to proceed through an oxidative radical cyclization mechanism and shows excellent functional group tolerance." ... 

Sano D, Nagata K, Itoh T. Catalytic asymmetric hydroxyl-ation of oxindoles by molecular oxygen using a phase-transfer catalyst. Org. Lett. 2008 10(8) 1593-1595. 

The conversion of indoles to oxindoles can be achieved in several ways. Reaction of indoles with a halogenaling agent such as NCS, NBS or pyridin-ium bromide perbromide in hydroxylic solvents leads to oxindoles[l]. The reaction proceeds by nucleophilic addition to a 3-haloindolenium intermediate. 

Batch reactors based on peroxidases are mainly applied for degradation purposes (see Chap. 8). LiP, manganese peroxidase (MnP), HRP, SBP, and CPO were used for the oxidation of phenolic compounds [3, 6, 7, 9, 20, 38, 74, 75, 95], decoloriza-tion of dye-containing effluents [5, 22], and pulp biobleaching [59]. In the field of synthesis, CPO is the most versatile and promising of the peroxidases (see Chap. 6). It was applied in discontinuous operation for epoxidations [78,79], enantioselective oxidations of alcohols to aldehydes [14,48], halogenations [77,80], hydroxylations, and oxidation of indole to oxindole, which is an important drug precursor [96]. 

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). 

When phenyl glycine ortho-caxhoxyMc acid is fused with potassium hydroxide it first loses water yielding an acid, indoi llic acid, and this loses carbon dioxide yielding indoxyl. In indoxyl the hydroxyl group is in the 3-position while in the isomeric oxindole it is in the 2-position. All of these comp>ounds are thus condensed hetero-cyclic compounds of a benzene ring and a pyrrole ring. Indole is the mother substance and the others are hydroxy or ketone derivatives. 

In 2012, Ye, Jiao, and co-workers described the first application of iV-aryl isatin imines as the electrophiles in NHC-catalyzed homoenolate additions, providing a simple and efficient approach to spirocyclic y-lactam oxindoles. Utilizing the catalyst with free hydroxyl group first developed in the Ye group, an asymmetric variant of this reaction was demonstrated in a moderate enantioselective manner (80% yield, 6 1 dr, 74% ee) (Scheme 7.48). 

Hypervalent iodine reagents have successfully been employed in the oxidative functionalization of enolizable carbonyl compounds over the years [6]. This methodology has allowed the construction of diverse C-C bonds in the context of heterocychc synthesis and has enriched the otherwise rare repertoire of such chemistry. Zhao, Du, and coworkers [37] have recendy realized a metal-free PIFA-mediated synthesis of 3-hydroxy-2-oxindoles 34 and spirooxindoles 35 starting from anilide derivatives 33 (Scheme 8 (1)). These processes showcase an oxidative cross coupling between an aromatic carbon and a pendant aliphatic carbon, followed by further oxidative hydroxylation or spirocycUzation. Later, the authors extended the same concept to achieve C(sp )-C(sp ) bond formation, where anilide derivatives possessing terminal enol functionality underwent PIDA-... 

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