3-Hydroxy-2-oxindoles, synthesis

A unique oxindole synthesis is the addition of diphenylketene to the mono-A-phenylimine of benzoquinone the resulting spiro-P-lactam (18) rearranges to give a 62% overall yield of 5-hydroxy-l,3,3-triphenyloxindole (19), which can be methylated to the 5-methoxy compound,35 which in turn could be converted to the Fischer s base. 

V. P. Kumar, V. P. Reddy, S. Sridhar, B. Srinivas, M. Narender, K. R. Rao, Supramolecular synthesis of 3-indolyl-3-hydroxy oxindoles under neutral conditions in water, J. Org. Chem., 2008, 73, 1646-1648. 

Hosseini-Sarvari, M. and Tavakolian, M. 2012b. Preparation, characterization, and catalysis application of nano-rods zinc oxide in the synthesis of 3-indolyl-3-hydroxy oxindoles in water. Appl. Catal. A Gen. 441-442 65-71. 

Recently, Wang et al. reported the reaction of isatins with nitromethane using C6 -OH cinchona alkaloid catalyst 15 (Scheme 29.8). 3-Substituted 3-hydroxy-oxindoles are obtained in excellent yields and enantioselectivities albeit long reaction times are required [22]. For the 4,7-dichloroisatin and N-benzyl-isatin, only moderate enantioselectivities were obtained (71% and 76%, respectively). The methodology was applied to the total synthesis of (R)-(+)-dioxibrassinin (20) and the formal synthesis of (S)-(-)-spirobrassinin (21). 

The Martinet procedure for the synthesis of indole-2,3-diones involves the reaction of an aminoaromatic compound and either an oxomalonate ester or its hydrate in the presence of an acid to yield a 3-(3-hydroxy-2-oxindole)carboxylic acid derivative which after oxidative decarboxylation yields the respective isatin. This method was applied with success for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful40 (Scheme 9). 

Grant and Krische have described a racemic protocol for the synthesis of allcarbon C3 quaternary centers from 3-hydroxy-3-tert-prenyloxindole 76 that was accessed via ruthenium catalyzed addition of 1,1-dimethylallene 75 to isatin 74 [45]. As outlined in Scheme 21, 76 was converted to the electrophilic 3-chloro derivative, which was trapped with indole under basic conditions to afford 78 in 60% yield. A mechanism has been proposed for the C-C bond-forming event that involved first-order irmizatirHi of chloride irm assisted by delocaUzatiOTi of oxindole... 

The attempted total synthesis " of 6-hydroxy-2 -(2-methylpropyl)-3,3 -spiro-(tetrahydropyrrolidino)-oxindole (127), an alkaloid of the dried root bark of Eleagnus communis (Wolf willow, or silverberry), " resulted in the formation of the epimer (128), or a mixture of (127) and (128) (Scheme 14). The final product showed great similarity to, but was not identical with, the alkaloid (127) however, (127) and the synthetic material gave the same product on acetylation, the reaction conditions for which presumably allowed epimerization at C-2. ... 

Additional examples of synthetic applications of hypervalent iodine-induced heterocyclizations include the following the metal-free one-pot synthesis of 2-acylbenzothiazoles by oxidative cyclization of multiform substrates [434], iodine(III)-mediated tandem oxidative cyclization for construction of 2-nitrobenzo[ ]furans [435], hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzo- and naphthofu-rans [436], PhI(OCOCF3)2-mediated synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from anilides [437], synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes [438],... 

The first example of direct enantioselective addition of a C—H bond to a ketone was reported by Shibata and co-workers in 2009 using the cationic Ir/ (S)-Hg-BINAP as the catalyst in the synthesis of a chiral 4-acetyl-3-hydroxy-3-methyl-2-oxindole with 72% ee. Recently, Yamamoto and co-workers developed a cationic Ir/(R,R)-Me-BIPAM catalyzed asymmetric intramolecular direct hydroarylation of a-keto amides 178 affording the chiral 3-substi-tuted 3-hydroxy-2-oxindoles 179 in high yields with complete regioselectivity and high enantioselectivity (84-98% ee). In their proposed reaction mechanism, the aryl iridium complex formed via C—H bond activation is coordinated with the two carbonyl groups of the amide (Scheme 5.65). 

An interesting enantioselective copper-catalyzed coupling of pyrroles 261 with isatins 260 was reported for the synthesis of 3-substituted-3-hydroxy-2-oxindoles 262. This reaction proceeds in moderate to high yield with high ee (140L3192). 

Scheme 2.8 The total synthesis of the S-hydroxy-2-oxindole derivatives.

The heterogeneous catalyst kaolin, preloaded with KOH, was used for the synthesis of 3-hydroxy-3-indolyl oxindoles from isatins and indoles in good to excellent yields by Srihari and Murthy (2011) (Scheme 2.15). The feasibility of the reaction was studied in various organic solvents such as CH2CI2, CH3CN, DMF, MeOH, and DMSO and found that the reaction did not proceed in CH2CI2, DMF, and DMSO, whereas the... 

Srihari, G. and Murthy, M. M. 2011. Kaolin/KOH is an efficient heterogeneous catalyst for the synthesis of 3-hydroxy-3-indolyl oxindoles. Synth. Common. 41(18) 2684—2692. 

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-... 

Nakamura et al. established the stereoselective synthesis of 3-hydroxy-2-oxindols by using 1,7-asymmetric induction. Scheme 8.51 shows the enantioselective synthesis of convo-lutamydine B 310, an antitumor agent. The vinylogous aldol reaction with dienolate 303 and enf-303 was found to be effective to yield 3-hydroxy-2-oxindols stereoselectively. 

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